EP1531822B1 - 1-aryl-4-substituierte piperazin-derivate zur verwendung als ccr1-antagonisten zur behandlung von entzündungen und immunerkrankungen - Google Patents

1-aryl-4-substituierte piperazin-derivate zur verwendung als ccr1-antagonisten zur behandlung von entzündungen und immunerkrankungen Download PDF

Info

Publication number
EP1531822B1
EP1531822B1 EP03737057A EP03737057A EP1531822B1 EP 1531822 B1 EP1531822 B1 EP 1531822B1 EP 03737057 A EP03737057 A EP 03737057A EP 03737057 A EP03737057 A EP 03737057A EP 1531822 B1 EP1531822 B1 EP 1531822B1
Authority
EP
European Patent Office
Prior art keywords
alkyl
group
chloro
phenyl
haloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP03737057A
Other languages
English (en)
French (fr)
Other versions
EP1531822A1 (de
Inventor
Andrew M. K. Pennell
James B. Aggen
J. J. Kim Wright
Subhabrata Sen
Brian E. Mcmaster
Daniel Joseph Dairaghi
Valeri V. Martichonok
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chemocentryx Inc
Original Assignee
Chemocentryx Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chemocentryx Inc filed Critical Chemocentryx Inc
Publication of EP1531822A1 publication Critical patent/EP1531822A1/de
Application granted granted Critical
Publication of EP1531822B1 publication Critical patent/EP1531822B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/16—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention provides compounds, pharmaceutical compositions containing one or more of these compounds or their pharmaceutically acceptable salts, which are effective in inhibiting the binding of various chemokine, such as MIP-1 ⁇ , leukotactin, MPIF-1 and RANTES, to the CCR1 receptor.
  • various chemokine such as MIP-1 ⁇ , leukotactin, MPIF-1 and RANTES
  • the compounds and compositions have utility in treating inflammatory and immune disorder conditions and diseases.
  • the immune system which comprises leukocytes (white blood cells (WBCs): T and B lymphocytes, monocytes, macrophages granulocytes, NK cell, mast cells, dendritic cell, and immune derived cells (for example; osteoclasts)), lymphoid tissues and lymphoid vessels, is the body's defense system.
  • WBCs white blood cells
  • monocytes monocytes
  • macrophages macrophages granulocytes
  • NK cell mast cells
  • dendritic cell dendritic cell
  • immune derived cells for example; osteoclasts
  • Chemokines act as molecular beacons for the recruitment and activation of immune cells, such as lymphocytes, monocytes and granulocytes, identifying sites where pathogens exist.
  • chemokine signaling can develop and has been attributed to triggering or sustaining inflammatory disorders, such as rheumatoid arthritis, multiple sclerosis and others.
  • rheumatoid arthritis unregulated chemokine accumulation in bone joints attracts and activates infiltrating macrophages and T-cells.
  • the activities of these cells induce synovial cell proliferation that leads, at least in part, to inflammation and eventual bone and cartilage loss (see, DeVries, M.E., et al., Semin Immunol 11(2):95-104 (1999 )).
  • chemokine-mediated monocyte/macrophage and T cell recruitment to the central nervous system A hallmark of some demyelinating diseases such as multiple sclerosis is the chemokine-mediated monocyte/macrophage and T cell recruitment to the central nervous system (see, Kennedy, et al., J. Clin. Immunol. 19(5):273-279 (1999 )). Chemokine recruitment of destructive WBCs to transplants has been implicated in their subsequent rejection. See, DeVries, M.E., et al., ibid Because chemokines play pivotal roles in inflammation and lymphocyte development, the ability to specifically manipulate their activity has enormous impact on ameliorating and halting diseases that currently have no satisfactory treatment. In addition, transplant rejection may be minimized without the generalized and complicating effects of costly immunosuppressive pharmaceuticals:
  • Chemokines a group of greater than 40 small peptides (7-10 kD), ligate receptors expressed primarily on WBCs or immune derived cells, and signal through G-protein-coupled signaling cascades to mediate their chemoattractant and chemostimulant functions.
  • Receptors may bind more than one ligand; for example, the receptor CCR1 ligates RANTES (regulated on activation normal T cell expressed), MIP-1 ⁇ (macrophage inflammatory p rotein), MPIF-1/CK ⁇ , and Leukotactin chemokines (among others with lesser affinities).
  • 24 chemokines receptors are known.
  • Chemokine activity can be controlled through the modulation of their corresponding receptor, treating related inflammatory and immunological diseases and enabling organ and tissue transplants.
  • the receptor CCR1 and its chemokine ligands represent significant therapeutic targets (see Saeki, et al., Current Pharmaceutical Design 9:1201-1208 (2003 )) since they have been implicated in rheumatoid arthritis, transplant rejection (see, DeVries, M.E., et al., ibid.), and multiple sclerosis (see, Fischer, et al., J Neuroimmunol. 110(1-2):195-208 (2000 ); Izikson, et al J. Exp. Med 192(7):1075-1080 (2000 ); and Rottman, et al., Eur.
  • the present invention provides the use of a compound having the formula: or a pharmaceutically acceptable salt thereof in the manufacture of in the manufacture of a medicament for use in a method of treating CCR1 mediated diseases or conditions comprising administering to a subject in need thereof a therapeutically effective amount of said compound.
  • the subscript n represents an integer of from 1 to 2, preferably 1 .
  • the subscript m represents an integer of from 0 to 10, limited by the number of available substituents positions on the piperazine or homopiperazine ring to which it is attached.
  • piperazine derivatives (n is 1) can have from 0 to 8 R 1 groups, preferably 0 to 4 R 1 groups, and more preferably, 0, 1 or 2 R 1 groups.
  • Each R 1 is a substituent independently selected from C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 2-8 alkenyl and C 2-8 alkynyl, -COR a , -CO 2 R 3 , -CONR a R b , -NR a COR b , -SO 2 R a , -X 1 CO 2 R a , -X 1 CONR a R b , -X 1 NR a COR b , -X 1 SO 2 R a , -X 1 SO 2 NR a R b , X 1 NR a R b , -X 1 OR a , wherein X 1 is a member selected from the group consisting Of C 1-4 alkylene, C 2-4 alkenylene and C 2-4 alkynylene and each R a and R b is independently selected from the group consisting of hydrogen, C 1-8 alkyl, C
  • Ar 1 represents phenyl substituted with from one to three R 2 substituents independently selected from halogen, -OR c , -OC(O)R c , -NR c R d , -SR c , -R e , -CN, -NO 2 , -CO 2 R c , -CONR c R d , -C(O)R c , -OC(O)NR c R d , -NR d C(O)R c , -NR d C(O) 2 R c , -NR c -C(O)NR c R d , -S(O)R e , -S(O) 2 R e , -NR c S(O) 2 R e , -S(O) 2 NR c R d and -N 3 wherein each R c and R d is independently selected from hydrogen, C 1-8 alkyl, C 1
  • HAr represents an optionally substituted heteroaryl group selected from the group consisting of pyrazolyl and benzopyrazolyl and is bound to the remainder of the molecule via a nitrogen atom of the pyrazolyl ring or via a nitrogen atom of the pyrazole portion of the fused ring respectively, each of which is substituted with from one to five R 3 substituents independently selected from the group consisting of halogen, phenyl, thienyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, -OR f , - OC(O)R f , -NR f R g , -SR f , -R h
  • L 1 represents a -CH 2 - and is optionally substituted with phenyl, -R k , -X 4 OR i , -X 4 OC(O)R i , -X 4 NR i R j , -X 4 SR i , -X 4 CN or -X 4 NO 2
  • X 4 is selected from the group consisting of C 1-4 alkylene, C 2-4 alkenylene and C 2-4 alkynylene and each R i and R j is independently selected from hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3 - 6 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, aryl-C 1-4 alkyl, and aryloxy-C 1-4 alkyl, and each R k is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 3-6
  • the present invention further provides compounds and pharmaceutical compositions containing one or more of these compounds.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e. C 1-8 means one to eight carbons).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • alkenyl refers to an unsaturated alkyl group having one or more double bonds.
  • alkynyl refers to an unsaturated alkyl group having one or more triple bonds.
  • unsaturated alkyle groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • cycloalkyl refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C 3-6 cycloalkyl) and being fully saturated or having no more than one double bond between ring vertices.
  • Cycloalkyl is also meant to refer to bicyclic and polycyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.
  • alkylene by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH 2 CH 2 CH 2 CH 2 -.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having four or fewer carbon atoms.
  • alkoxy alkylamino and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. Additionally, for dialkylamino groups, the alkyl portions can be the same or different and can also be combined to form a 3-7 membered ring with the nitrogen atom to which each is attached. Accordingly, a group represented as -NR a R b is meant to include piperidinyl, pyrrolidinyl, morpholiny), azetidinyl and the like.
  • halo or halogen
  • substituents mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
  • C 1-4 haloalkyl is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • aryl means, unless otherwise stated, a polyunsaturared, typically aromatic, hydrocarbon group which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
  • heteroaryl refers to aryl groups (or rings) that contain from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl, while non-limiting examples of heteroaryl groups include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazoly], 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, benzopyrazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinoly
  • aryl when used in combination with other terms (e.g ., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g ., benzyl, phenethyl, pyridylmethyl and the like).
  • alkyl in some embodiments, will include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
  • aryl and heteroaryl will refer to substituted or unsubstituted versions as provided below, while the term “alkyl” and related aliphatic radicals is meant to refer to unsubstituted version, unless indicated to be substituted.
  • -NR'C(NH 2 ) NH
  • -NH-C(NH 2 ) NR', -S(O)R', -S(O) 2 R', -S(O) 2 NR'R", -NR'S(O) 2 R", -CN and -NO 2 in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical.
  • R', R" and R"' each independently refer to hydrogen, unsubstituted C 1-8 alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C 1-8 alkyl, C 1-8 alkoxy or C 1-8 thioalkoxy groups, or unsubstituted aryl-C 1-4 alkyl groups.
  • R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-,6-, or 7-membered ring.
  • -NR'R is meant to include 1-pyrrolidinyl and 4-morpholinyl.
  • R', R" and R"' are independently selected from hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C 1-4 alkyl, and unsubstituted aryloxy-C 1-4 alkyl.
  • R', R" and R"' are independently selected from hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C 1-4 alkyl, and unsubstituted aryloxy-C 1-4 alkyl.
  • Other suitable substituents include each of the above aryl substituents attached to a ring atom by an alkylene tether of from 1-4 carbon atoms.
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CH 2 ) q -U-, wherein T and U are independently -NH-, -O-, -CH 2 - or a single bond, and q is an integer of from 0 to 2.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CH 2 -, -O-, -NH-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'- or a single bond, and r is an integer of from 1 to 3.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH 2 ) s -X-(CH 2 ) t -, where s and t are independently integers of from 0 to 3, and X is -O-, -NR'-, -S-, - S(O)-, -S(O) 2 -, or -S(O) 2 NR'-.
  • the substituent R' in -NR'- and -S(O) 2 NR'- is selected from hydrogen or unsubstituted C 1-6 alkyl.
  • heteroatom is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
  • salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • salts derived from phannaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally- occuring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucasamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resin, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S.M., et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19 ).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention
  • Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, arc intended to be encompassed within the scope of the present invention.
  • the present invention derives from the discovery that compounds of formula I (as well as the subgeneric formulae II, III and IV) act as potent antagonists of the CCR1 receptor. This antagonist activity has been further confirmed in animal testing for inflammation, one of the hallmark disease states for CCR1. Accordingly, the compounds provided herein are useful in pharmaceutical compositions, methods for the treatment of CCR1-mediated diseases, and as controls in assays for the identification of competitive CCR1 antagonists.
  • the compounds used in the present invention have the formula: or a pharmaceutically acceptable salt thereof.
  • n represents an integer of from 1 to 2, preferably 1.
  • m represents an integer of from 0 to 10, limited by the number of available substituents positions on the piperazine or homopiperazine ring to which it is attached.
  • piperazine derivatives (n is 1) can have from 0 to 8 R 1 groups, preferably 0 to 4 R 1 groups, and more preferably, 0, 1 or 2 R 1 groups.
  • Ar 1 represents phenyl substituted with from one to three R 2 substituents independently selected from halogen, -OR c , -OC(O)R c , -NR c R d , -SR c , -R c -CN, -NO 2 , -CO 2 R c , -CONR c R d , -C(O)R c , -OC(O)NR c R d , -NR d C(O)R c , -NR d C(O) 2 R c , -NR c -C(O)NR c R d , -S(O)R e , -S(O) 2 R c , -NR c S(O) 2 R e , -S(O) 2 NR c R d and -N 3 wherein each R c and R d is independently selected from hydrogen, C 1-8 alkyl, C 1-8 alky
  • HAr is a heteroaryl group selected from the group consisting of pyrozolyl and benzopyrazolyl and is bound to the remainder of the molecule via a nitrogen atom of the pyrazolyl ring or via a nitrogen atom of the pyrazole portion of the fused ring system respectively, each of which is substituted with from one to five R 3 substituents independently selected from the group consisting of halogen, phenyl, thienyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, -OR f , -OC(O)R f , -NR f R g , -SR f , -R h , -
  • L 1 represents a linking group which is -CH 2 - optionally substituted with -R k , -X 4 OR i , -X 4 OC(O)R i , -X 4 NR i R j , -X 4 SR i , -X 4 CN or -X 4 NO 2 , wherein X 4 is selected from the group consisting of C 1-4 alkylene, C 2-4 alkenylene and C 2-4 alkynylene.
  • each R i and R j is independently selected from hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, aryl-C 1-4 alkyl, and aryloxy-C 1-4 alkyl
  • each R k is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, heteroaryl, aryl-C 1-4 alkyl, and aryloxy-C 1-4 alkyl.
  • the linking group is unsubstituted, while in other preferred embodiments, substituents are present that can increase partitioning into selected solvents or into selected tissues.
  • each R 1 is a substituent independently selected from C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 2-8 alkenyl and C 2-8 alkynyl, -COR a , -CO 2 R a , -CONR 3 R b , -NR a COR b , -SO 2 R a , -X 1 COR a .
  • X 1 is a member selected from the group consisting of C 1-4 alkylene, C 2-4 alkenylene and C 2-4 alkynylene and each R a and R b is independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 1-8 haloalkyl and C 3-6 cycloalkyl, and wherein the aliphatic portions of each of said R 1 substituents is optionally substituted with from one to three members selected from the group consisting of OH, O(C 1-8 alkyl), SH, S(C 1-8 alkyl), CN, NO 2 , NH 2 , NH(C 1-8 alkyl) and N(C
  • the compounds are represented by formula I in which Ar 1 is phenyl substituted with from 1 to 3 R 2 groups wherein Ar 1 is selected from those represented by: wherein Hal is F, Cl or Br and each R is independently C 1-6 alkyl or C 3-6 cycloalkyl.
  • HAr is selected from pyrazolyl optionally substituted from one to three R 3 groups independently selected from halogen, phenyl, thienyl, -OR f , -OC(O)R f , -NR f R g , -SR f , -R h , -CN, -NO 2 , -CO 2 R f , -CONR f R g , -C(O)R f , -OC(O)NR f R g , -NR g C(O)R f , -NR g C(O) 2 R h , -NR f -C(O)NR f R g , -S(O)R h , -S(O) 2 Rh, -S(O) 2 NR f R g , -NR f S(O) 2 R h , -NR f S(O) 2 NR f R g
  • n 1, m is 0, 1 or 2
  • Ar 1 is phenyl substituted with from one to three R 2 groups
  • HAr is pyrazolyl which is substituted with three R 3 groups
  • L 1 is -CH 2 -.
  • Ar 1 is selected from those substituted phenyl moieties provided in Figure 1 .
  • the compounds are represented by formula I in which Ar 1 is selected from phenyl, substituted with from one to three R 2 substituents wherein each R 2 is a member independently selected from the group consisting of halogen.
  • the compounds are represented by formula I in which HAr is selected from pyrazolyl and, benzopyrazolyl, each of which is optionally substituted with from one to five R 3 groups independently selected from the group consisting of halogen, phenyl, thienyl, -OR f , -COR f , -CO 2 R f , -CONR f R g , -NO 2 , -R h , -CN, -SR f , -S(O)R h , -S(O) 2 R h and -NR f R g , wherein R f and R g are each independently selected from the group consisting of H, C 1-8 alkyl, C 3-6 cycloalkyl and C 1-8 haloalkyl, and each R h is independently selected from the group consisting of C 1-8 alkyl, C 3-6 cycloalkyl and C 1-8 haloalkyl, and each R h is
  • the compounds are represented by formula II: or a pharmaceutically acceptable salt thereof, wherein each of R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g and R 1h represents a member independently selected from the group consisting of H, C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 2-8 alkenyl and C 2-8 alkynyl.
  • the remaining groups have the meanings provided above with reference to formula I in their most complete interpretation.
  • L 1 is -CH 2 - optionally substituted with one or more substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl and phenyl.
  • HAr is selected from pyrazolyl and benzopyrazolyl, each of which is optionally substituted with from one to five R 3 groups independently selected from halogen, phenyl, thienyl, -OR f , -OC(O)R f , -NR f R g , -SR f , -R h , -CN, -NO 2 , -CO 2 R f , -CONR f R g , -C(O)R f , -OC(O)NR f R g , -NR g C(O)R f , -NR g C(O) 2 R h , -NR f -C(O)NR f R
  • HAr is pyrazolyl or benzopyrazolyl, each of which is optionally substituted with from one to three R 3 groups independently selected from halogen, phenyl, thienyl, -OR f , -CO 2 R f , -COR f , -CONR f R g , -NO 2 , -R h , -CN, SR f , -S(O)R h , -S(O) 2 R h and -NR f R g , wherein each R f and R g is independently selected from H, C 1-8 alkyl and C 1-8 haloalkyl, each R h is independently selected from C 1-8 alkyl and C 1-8 haloalkyl. Most preferably, HAr is selected from the substituted pyrazolyl moieties provided in Figures 2 and 3 .
  • the compound is represent by formula II above, wherein Ar 1 is phenyl substituted with from one to three R 2 substituents independently selected from the group consisting of halogen, -OR c , -OC(O)R c , -NR c R d , -SR c , -R c , -CN, -NO 2 , -CO 2 R c , -CONR c R d , -C(O)R c , -OC(O)NR c R d , -NR d C(O)R c , -NR d C(O) 2 R c , -NR c -C(O)NR c R d , -S(O)R c , -S(O) 2 R e , -S(O) 2 NR c R d and -N 3 wherein each R c and R d is independently selected from hydrogen,
  • each R 1 is selected from C 1-4 alkyl and C 1-4 haloalkyl
  • R 2a , R 2b , R 2c , R 2d and R 2e are each members independently selected from hydrogen, halogen -OR c , -OC(O)R c , -NR c R d , -SR c , -R e , -CN, NO 2 , -CO 2 R c , -CONR c R d , -C(O)R c , -OC(O)NR c R d , -NR d C(O)R c , -NR d C(O) 2 R e , -NR c -C(O)NR c R d , -S(O)R e , -S(
  • the subscript m is 0 or 1 and at least one of R 2a or R 2e is hydrogen. More preferably, at least one of R 3a , R 3b and R 3c is selected from halogen and C 1-4 haloalkyl. Still more preferably, R 2d is hydrogen and at least two of R 3a , R 3b and R 3c are selected from halogen and C 1-4 haloalkyl with the remaining member being other than hydrogen.
  • m is 0 or 1 and at least one of R 2a or R 2e is hydrogen, R 2d is hydrogen, R 2c is selected from F, Cl, Br, CN, NO 2 , CO 2 CH 3 , C(O)CH 3 and S(O) 2 CH 3 , and at least two of R 3a , R 3b and R 3c are selected from halogen and C 1-4 haloalkyl with the remaining member being other than hydrogen.
  • the subscript m is 0 or 1; and R 2a and R 2e are both hydrogen. More preferably, at least one of R 3a , R 3b and R 3c is selected from halogen and C 1-4 haloalkyl.
  • R 3a , R 3b and R 3c is selected from halogen and C 1-4 haloalkyl, and the remaining members of R 3a , R 3b and R 3c are other than hydrogen.
  • the subscript m is 0 or 1; and R 2b and R 2c are both hydrogen.
  • at least one of R 3a , R 3b and R 3c is selected from halogen and C 1-4 haloalkyl.
  • at least one of R 3a , R 3b and R 3c is selected from halogen and C 1-4 haloalkyl, and the remaining members of R 3a , R 3b and R 3c are other than hydrogen.
  • R 3b is preferably halogen, nitro or cyano, more preferably halogen and most preferably chloro or bromo;
  • R 3c is preferably C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl;
  • R 2c is halogen and R 2b is -OR c or R e wherein R c is selected from hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 2-8 alkenyl and C 2-8 alkynyl, and R e is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 2-8 alkenyl and C 2-8 alkynyl, and each of R c and R e is optionally further substituted with from one to three members selected from the group consisting of OH, O(C 1-8 alkyl), SH, S(C
  • R 3b is preferably halogen, nitro or cyano, more preferably halogen and most preferably chloro or bromo;
  • R 3a is preferably C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl;
  • R 2c is preferably halogen and R 2b is preferably -OR c or R c wherein R c is selected from hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 2-8 alkenyl and C 2-8 alkynyl, and R c is selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 2-8 alkenyl and C 2-8 alkynyl, and each of R c and R e is optionally further substituted with from one to three members selected from the group consisting of OH, O(C 1-8 alkyl), SH, S(
  • R 3a is selected from NH 2 , CF 3 , SCH 3 , Ph and thienyl;
  • R 3b is chloro or bromo;
  • R 3c is preferably C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl;
  • R 2c is hydrogen, halogen, cyano or nitro; and
  • R 2b is selected from hydrogen, halogen.
  • R c and R d is independently selected from hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 2-8 alkenyl and C 2-8 alkynyl
  • each R e is independently selected from the group consisting of C 1-8 alkyl, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 2-8 alkenyl and C 2-8 alkynyl
  • each of R c , R d and R e is optionally further substituted with from one to three members selected from the group consisting of OH, O(C 1-8 al
  • R 2c is halogen, cyano or nitro
  • R 2b is R e or -OR c
  • R 3a is selected from the group consisting of NH 2 , CF 3 , SCH 3 , Ph and thienyl
  • R 3b is chloro or bromo
  • R 3c is selected from the group consisting of C 1-6 alkyl and C 3-6 cycloalkyl.
  • R 3c is selected from NH 2 , CF 3 , SCH 3 , Ph and thienyl;
  • R 3b is chloro or bromo;
  • R 3a is preferably C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl;
  • R 2c is hydrogen, halogen, cyano or nitro, preferably halogen; and
  • R 2b is selected from hydrogen, halogen, -OR c , -OC(O)R c , -NR c R d , -SR c , -R e , -CO 2 R c , -CONR c R d , -C(O)R c , -S(O)R e and -S(O) 2 R e , wherein R c and R d is independently selected from hydrogen, C 1-8 alkyl, C 1-8 haloalkyl, C
  • R 2c is halogen, cyano or nitro
  • R 2b is R e or -OR c
  • R 3a is selected from the group consisting of C 1- 6 alkyl and C 3-6 cycloalkyl
  • R 3c is selected from the group consisting of NH 2 , CF 3 , SCH 3 , Ph and thienyl
  • R 3b is chloro or bromo.
  • R 3a is selected from NH 2 , CF 3 , SCH 3 , Ph and thienyl;
  • R 3b is chloro or bromo;
  • R 3c is preferably C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl;
  • R 2a is preferably other than hydrogen, and is selected from halogen, -OR c , -OC(O)R c , -NR c R d , -SR c , -R e , -CO 2 R c , -CONR c R d , -C(O)R c , -S(O)R e and -S(O) 2 R e ;
  • R2 c is hydrogen, halogen, cyano or nitro, preferably halogen; and
  • R 2d is selected from hydrogen, halogen, -OR c , -OC(O)R c , -NR
  • each of R 2a and R 2d is other than hydrogen.
  • R 2a is other than hydrogen
  • R 2c is halogen, cyano or nitro
  • R 2d is R e or -OR c
  • R 3a is selected from the group consisting of C 1-6 alkyl and C 3-6 cycloalkyl
  • R 3b is chloro or bromo
  • R 3c is selected from the group consisting of NH 2 , CF 3 , SHC 3 , Ph and thienyl.
  • R 3c is selected from NH 2 , CF 3 , SCH 3 , Ph and thienyl;
  • R 3b is chloro or bromo;
  • R 3a is preferably C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl;
  • R 2a is hydrogen, halogen, -OR c , -OC(O)R c , -NR c R d , -SR c , -R e , -CO 2 R c , -CONR c R d , -C(O)R c , -S(O)R e and -S(O) 2 R e ;
  • R 2c is hydrogen, halogen, cyano or nitro; and
  • R 2d is selected from hydrogen, halogen, -OR c , -OC(O)R c , -NR c R d , -SR
  • each of R 2a and R 2d is other than hydrogen.
  • R 20 is other than hydrogen;
  • R 2c is halogen, cyano or nitro;
  • R 2d is R e or -OR c ;
  • R 3a is selected from the group consisting of NH 2 , CF 3 , SCH 3 , Ph and thienyl;
  • R 3b is chloro or bromo;
  • R 3c is selected from the group consisting of C 1-6 alkyl and C 3-6 cycloalkyl.
  • compositions for modulating CCR1 activity in humans and animals will typically contain a pharmaceutical carrier or diluent.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions for the administration of the compounds of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy and drug delivery. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self emulsifications as described in U.S. Patent Application 20020012680 , hard or soft capsules, syrups, elixirs, solutions, buccal patch, oral gel, chewing gum, chewable tablets, effervescent powder and effervescent tablets.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, antioxidants and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example PVP, cellulose, PEG, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated, enterically or otherwise, by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed, They may also be coated by the techniques described in the U.S. Pat. Nos. 4,256,108 ; 4,1666,452 ; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • emulsions can be prepared with a non-water miscible ingredient such as oils and stabilized with surfactants such as mono-diglycerides, PEG esters and the like.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monoole
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived form fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG and surfactants.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such material include cocoa butter and polyethylene glycols.
  • the compound can be administered via ocular delivery by means of solutions or ointments.
  • transdermal delivery of the subject compounds can be accomplished by means of iontophoretic patches and the like.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed.
  • topical application is also meant to include the use of mouth washes and gargles.
  • the present invention concerns treating CCR1-mediated conditions or diseases by administering to a subject having such a disease or condition, a therapeutically effective amount of a compound of formula I above.
  • the "subject” is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like.
  • CCR1 provides a target for interfering with or promoting specific aspects of immune cell functions, or more generally, with functions associated with CCR1 expression on a wide range of cell types in a mammal, such as a human.
  • Compounds that inhibit CCR1 are particularly useful for modulating monocyte, macrophage, lymphocyte, granulocyte, NK cell, mast cells, dendritic cell, and certain immune derived cell (for example, osteoclasts) function for therapeutic purposes.
  • the present invention is directed to compounds which are useful in the prevention and/or treatment of a wide variety of inflammatory and immunoregulatory disorders and diseases (see Saeki, et al., Current Pharmaceutical Design 9:1201-1208 (2003 )).
  • an instant compound that inhibits one or more functions of CCR1 may be administered to inhibit (i.e., reduce or prevent) inflammation or cellular infiltration associated with an immune disorder.
  • one or more inflammatory processes such as leukocyte emigration or infiltration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, can be inhibited.
  • monocyte infiltration to an inflammatory site e.g., an affected joint in arthritis, or into the CNS in MS
  • an inflammatory site e.g., an affected joint in arthritis, or into the CNS in MS
  • an instant compound that promotes one or more functions of CCR1 is administered to stimulate (induce or enhance) an inflammatory response, such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, resulting in the beneficial stimulation of inflammatory processes.
  • an inflammatory response such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, resulting in the beneficial stimulation of inflammatory processes.
  • monocytes can be recruited to combat bacterial infections.
  • the disease or condition is one in which the actions of immune cells such monocyte, macrophage, lymphocyte, granulocyte, NK cell, mast cell, dendritic cell, or certain immune derived cell (for example, osteoclasts) are to be inhibited or promoted, in order to modulate the inflammatory or autoimmune response.
  • immune cells such monocyte, macrophage, lymphocyte, granulocyte, NK cell, mast cell, dendritic cell, or certain immune derived cell (for example, osteoclasts) are to be inhibited or promoted, in order to modulate the inflammatory or autoimmune response.
  • diseases or conditions including chronic diseases, of humans or other species can treated with modulators of CCR1 function.
  • diseases or conditions include: (1) allergic diseases such as systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies and food allergies, (2) inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, ileitis and enteritis, (3) vaginitis, (4) psoriasis and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria and pruritus, (5) vasculitis, (6) spondyloarthropathies, (7) scleroderma, (8) asthma and respiratory allergic diseases such as allergic asthma, allergic rhinitis, hypersensitivity lung diseases and the like, (9) autoimmune diseases, such as fibromyalagia, scleroderma, ankylosing spondylitis, juvenile RA, Still's disease, poly
  • diseases or conditions can be treated with modulators of CCR1 function.
  • diseases to be treated with modulators of CCR1 function include cancers, cardiovascular diseases, diseases in which angiogenesis or neovascularization play a role (neoplastic diseases, retinopathy and macular degeneration), infectious diseases (viral infections, e.g. , HIV infection, and bacterial infections) and immunosuppressive diseases such as organ transplant conditions and skin transplant conditions.
  • organ transplant conditions is meant to include bone marrow transplant conditions and solid organ (e.g. , kidney, liver, lung, heart, pancreas or combination thereof) transplant conditions.
  • the compounds used in the present invention are accordingly useful in the prevention and treatment of a wide variety of inflammatory and immunoregulatory disorders and diseases.
  • the compounds may be administered by oral, parenteral, (e.g. , intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • parenteral e.g. , intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant
  • an appropriate dosage level will generally be 0.001 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be 0.01 to 25 mg/kg per day; more preferably 0.05 to 10 mg/kg per day.
  • a suitable dosage level may be 0.01 to 25 mg/kg per day, 0.05 to 10 mg/kg per day, or 0.1 to 5 mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per day.
  • the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0.
  • the compounds may be administered on a regimen of I to 4 times per day, preferably once or twice per day.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, hereditary characteristics, general health, sex and diet of the subject, as well as the mode and time of administration, rate of excretion, drug combination, and the severity of the particular condition for the subject undergoing therapy.
  • the compounds and compositions used in the present invention can be combined with other compounds and compositions having related utilities to prevent and treat the condition or disease of interest, such as inflammatory or autoimmune disorders, conditions and diseases, including inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, polyarticular arthritis, multiple sclerosis, allergic diseases, psoriasis, atopic dermatitis and asthma, and those pathologies noted above.
  • inflammatory or autoimmune disorders including inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, polyarticular arthritis, multiple sclerosis, allergic diseases, psoriasis, atopic dermatitis and asthma, and those pathologies noted above.
  • the present compounds and compositions may be used in conjunction with an anti-inflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide, a non steroidal anti-inflammatory agent, or a cytokine-suppressing anti-inflammatory agent, for example with a compound such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic,
  • an anti-inflammatory or analgesic agent such as an opiate agonist, a
  • the instant compounds and compositions may be administered with an analgesic listed above; a potentiator such as caffeine, an H2 antagonist (e.g. , ranitidine), simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, ephinephrine, naphazolinc, xylometazoline, propylhexedrine, or levo desoxy ephedrine; an antitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextromethorphan; a diuretic; and a sedating or non sedating antihistamine.
  • a potentiator such as caffeine, an H2 antagonist (e.g. , ranitidine), simethicone, aluminum or magnesium hydroxide
  • a decongestant such as phenylephrine, pheny
  • compounds and compositions used in the present invention may be used in combination with other drugs that are used in the treatment, prevention, suppression or amelioration of the diseases or conditions for which compounds and compositions of the present invention are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound or composition of the present invention.
  • a pharmaceutical composition containing such other drugs in addition to the compound or composition used in the present invention is preferred.
  • the pharmaceutical compositions include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound or composition used in the present invention
  • other therapeutic agents include, but are not limited to: (a) VLA-4 antagonists, (b) corticosteroids, such as beclomethasone, methylprednisolone, betamethasone, prednisone, prenisolone, dexamethasone, fluticasone, hydrocortisone, budesonide, triamcinolone, salmeterol, salmeterol, salbutamol, formeterol; (c) immunosuppressants such as cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (sirolimus, Rapamune®) and other FK-506 type immunosuppressants, and mycophenol
  • H1-histamine antagonists such as bromopheniramine, chlorpheniramine, dexchloipheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and the like; (e) non steroidal anti asthmatics (e.g.
  • terbutaline metaproterenol
  • fenoterol isoetharine, albutetol, bitolterol and pirbuterol
  • theophylline cromolyn sodium, atropine, ipratropium bromide
  • leukotriene antagonists e.g. , zafmlukast, montelukast, pranlukast, iralukast, pobilukast and SKB-106,203
  • leukotriene biosynthesis inhibitors zileuton, BAY-1005
  • non steroidal anti-inflammatory agents such as propionic acid derivatives (e.g.
  • alminoprofen alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen), acetic acid derivatives (e.g.
  • indomethacin acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin and zomepirac
  • fenamic acid derivatives e.g. , flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid
  • biphenylcarboxylic acid derivatives e.g.
  • oxicams e.g. , isoxicam, piroxicam, sudoxicam and tenoxican
  • salicylates e.g. , acetyl salicylic acid and sulfasalazine
  • pyrazolones e.g.
  • cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®) and rofecoxib (Vioxx®);
  • COX-2 (COX-2) inhibitors such as celecoxib (Celebrex®) and rofecoxib (Vioxx®);
  • PDE IV inhibitors of phosphodiesterase type IV (PDE IV);
  • gold compounds such as auranofin and aurothioglucose,
  • etanercept Enbrel®
  • antibody therapies such as orthoclone (OKT3), daclizumab (Zenapax®), basiliximab (Simulect®) and infliximab (Remicade®), (1) other antagonists of the chemokine receptors, especially CCR5, CXCR2, CXCR3, CCR2, CCR3, CCR4, CCR7, GX 3 CR1 and CXCR6;
  • vitamin D 3 derivatives e.g. , calcipotriene or calcipotriol (Dovonex®), (p) PUVA, (q) anthralin (Drithrocreme®); (r) etretinate (Tegison®) and isotretinoin and (s) multiple sclerosis therapeutic agents such as interferon ⁇ -1 ⁇ (Betaseron®), interferon ( ⁇ -1 ⁇ (Avonex®), azathioprine (Imurek®, Imuran®), glatiramer acetate (Capoxone®), a glucocorticoid (e.g.
  • DMARDS such as methotrexate (u) other compounds such as 5-aminosalicylic acid and prodrugs thereof; hydroxychloroquine; D-penicillamine; antimetabolites such as azathioprine, 6-mercaptopurine and methotrexate; DNA synthesis inhibitors such as hydroxyurea and microtubule disrupters such as colchicine.
  • the weight ratio of the compound used in the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • the weight ratio of the compound used in the present invention to the NSAID will generally range from 1000:1 to 1:1000, preferably 200:1 to 1:200.
  • Combinations of a compound used in the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). 1 H-NMR were recorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaks are tabulated in the order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) and number of protons. Mass spectrometry results are reported as the ratio of mass over charge, followed by the relative abundance of each ion (in parenthesis). In tables, a single m/e value is reported for the M+H (or, as noted, M-H) ion containing the most common atomic isotopes.
  • Electrospray ionization (ESI) mass spectrometry analysis was conducted on a Hewlett-Packard MSD electrospray mass spectrometer using the HP1100 HPLC for sample delivery. Normally the analyte was dissolved in methanol at 0.1 mg/mL and 1 microlitre was infused with the delivery solvent into the mass spectrometer, which scanned from 100 to 1500 daltons. All compounds could be analyzed in the positive ESI mode, using acetonitrile / water with 1% formic acid as the delivery solvent. The compounds provided below could also be analyzed in the negative ESI mode, using 2mM NH 4 OAc in acetonitrile / water as delivery system.
  • ESI Electrospray ionization
  • Two regioisomers can sometimes exist for certain compounds used in the invention.
  • compounds such as those of formula III can be prepared wherein the pyrazole moiety is linked to the remainder of the molecule via either of the nitrogen atoms in the pyrazole ring.
  • both regioisomeric types have demonstrated biological properties and are meant to be within the scope of all the appended claims, whether explicitly drawn or not.
  • the piperazine ring can be formally attached to the terminal aryl unit in a number of ways: by aromatic nuclephilic displacement reactions, metal catalyzed coupling reactions (arylation reactions of secondary amines), ring expansion, rearrangement and cyclization reactions and the like. Also, different protection / deprotection strategies can be utilized. Hence, either all or only part of the final molecular architecture can be present during the key aryl coupling step. Examples for a variety of such aryl coupling strategies are listed below.
  • PROTOCOL A Metal catalysed arylation reactions of secondary amines
  • reaction mixture was refluxed at 110°C for 20 hrs, filtered through a celite bed, washed with toluene, concentrated, taken in ethyl acetate and extracted with 1.5 (N) HCl solution three times.
  • the combined aqueous layers were washed with diethyl ether.
  • the aqueous layer was neutralized with 10% aqueous sodium hydroxide solution and then extracted with ethyl acetate three times.
  • the combined ethyl acetate layers were washed with water and saturated brine solution, dried over anhydrous sodium sulfate and concentrated. Purification by flash chromatography (eluted with CHCl3-MeOH) afforded the title compound as product.
  • Piperazine (0.588g, 6.84mmol), Pd(II)acetate (0.027g , 0.123mmol), sodium t-butoxide (0.837g, 10.06mmol) and BINAP (0.154g, 0.286mmol) were stirred at room temperature in 10 mL dry toluene for 15 min.
  • 4-trifluoromethoxy bromo benzene (1.5 g, 6.22mmol) in 10 mL dry toluene was added into the reaction mixture. Then the reaction mixture was refluxed at 110°C for 20 hrs.
  • reaction mixture was filtered through a celite bed, washed with toluene, concentrated, ethyl acetate added and then extracted with 1.5 (N) aqueous HCl solution three times.
  • the combined aqueous layers were washed with diethyl ether.
  • the aqueous layer was neutralized with 10% aqueous sodium hydroxide solution and then extracted with ethyl acetate three times.
  • the combined ethyl acetate layers were washed with water and saturated brine solution, dried over anhydrous sodium sulfate and concentrated to afford the product.
  • the toluene was concentrated and the reaction mixture was taken in ethyl acetate and extracted with 1.5 (N) HCl solution three times. The combined aqueous layers were washed with diethyl ether. The aqueous layer was neutralized with 10% aqueous sodium hydroxide solution and then extracted with ethyl acetate three times. The combined ethyl acetate layers were washed with water and saturated brine solution, dried over anhydrous sodium sulfate, concentrated and chromatographed (9/1-CHCl3/MeOH) to afford the product.
  • 1-Bromo-3-isopropoxy-4-chlorobenzene (preparation described elsewhere) was combined with 1.11g (6 mmol) of 1-Bocpiperazine, 672mg (7.0 mmol) of sodium tert-butoxide, 93mg (0.15 mmol) of rac-2,2'-Bis(diphenylphosphine)-1,1'-binaphthyl, and 45mg (0.05 mmol) Tris(dibenzylidencacetone)dipalladium (0) in a flask under an N2 atmosphere, and the mixture was heated at 85°C for 3.5 hours.
  • the resulting residue was partitioned between a 1/1 mixture of ether and ethyl acetate and water, and the phases were separated.
  • the final organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to an oil.
  • the oil was dissolved in ethyl acetate, 10mL each of 2M HCl in ether and methanol were added, and the product was isolated by filtration after crystallization.
  • a single neck round bottom flask was charged with 1-chloro-4-iodo benzene (1.0 g, 0.0041 mol) and R(-)-2-methylpiperazine (0.5 g, 0.005 mol), potassium t-butoxide (0.705 g, 0.0062 mol), tris(benzylideneacetone)dipalladium(0) (0.095 g, 0.0002 mol) and 1,3 bis(2,6-diisopropylphenyl)imidazole-2-ylidene) (0.073 g, 0.0001 mol).
  • the flask was evacuated and filled with nitrogen. Dry dioxane (20 mL) was added and stirred at 70 °C overnight.
  • reaction mixture was diluted with dichloromethane and filtered. Crude compound was purified by column chromatography. The compound was dissolved in ether and purged with HCl gas to yield 1-(4-Chloro-phenyl)-3-methyl-piperazine.
  • reaction mixture was filtered through a celite bed and washed with toluene, then concentrated and the reaction mixture was taken into ethyl acetate and extracted with 1.5 (N) HCl solution three times.
  • the combined aqueous layer was washed with diethyl ether.
  • the aqueous layer was neutralized with 10% aqueous sodium hydroxide solution and then extracted with ethyl acetate three times.
  • the combined ethyl acetate layers were washed with water and saturated brine solution, dried over anhydrous sodium sulfate, and concentrated to afford the product as a white solid.
  • PROTOCOL B Piperidine ring formation via cyclization reactions
  • 3,4-Difluoro-aniline (1g, 7.7mmol) was dissolved in dry n-butanol (10mL) and dry sodium carbonate (3.2g, 30mmol) was added to it and the reaction mixture stirred for 1. hour under nitrogen.
  • Bis(2-chloroethyl) amine hydrochloride (1.38g, 7.7mmol) in nBuOH (10mL) were then added to the mixture via a syringe. The reaction was then heated at 120°C for 48h. The nBuOH was evaporated in vacuo and the residue was extracted with ethyl acetate. Drying of the organic layer with Na 2 SO 4 followed by concentration afforded the crude product. Purification using flash column chromatography (chloroform/methanol) afforded 1-(3,4-Difluoro-phenyl)-piperazine as an off white solid.
  • PROTOCOL C Piperidine ring formation via a ring opening / ring cyclization strategy
  • the solution was then concentrated in vacuo to give a residue that was partitioned between ether and water.
  • the phases were separated, and the aqueous phase as basified with 1M NaOH.
  • the aqueous phase was then extracted twice with ethyl acetate.
  • the combined ethyl acetate phases were washed once with brine, dried over Na2S04, filtered, and acidified with 2M HCl in ether.
  • the product was isolated via filtration.
  • a direct halogen displacement strategy can be complimentary to the metal mediated approaches, discussed above, for the construction of the ring systems provided herein.
  • 4-bromoethyl benzoate (10:0 g, 0.0437 mol) was taken into 250 mL of dry DMF, piperazine (37g, 0.437 mol) was added, followed by 30g (0.2185 mol) of dry potassium carbonate, 1.0 g of TBAI and 1.5 g of potassium iodide.
  • the reaction mixture was heated at 135 °C for over night.
  • the reaction mixture was quenched with water and extracted with ethyl acetate.
  • the extracts were washed with water, then brine and then concentrated to yield 4-Piperazin-1-yl-benzoic acid ethyl ester as an off-white solid.
  • PROTOCOL D Synthesis and addition of elaborated piperazines to aryl and heteroaryl halides via aryl-halogen displacement methodologies
  • Functionalization of the aryl ring within the arylpiperazine ring system can, in general, take place either before or after introduction of the piperazine ring, as illustrated in the examples below.
  • PROTOCOLE Selected examples of halogenation of aromatic systems after attachment of the piperazine ring system
  • PROTOCOL F Selected examples of demethylation / etherification of aromatic precursors for attachment of the piperazine ring system to access key arylpiperazine moieties
  • PROTOCOL F Additional examples of analogous ring systems constructed using similar demethylation / etherification strategies.
  • PROTOCOL G General procedure for the synthesis of elaborated aryl bromides from anilines
  • the reaction mixture was cooled to room temperature and solid formed was washed with water to afford white solid cuprous bromide.
  • the diazonium salt was portion wise added into the freshly prepared cuprous bromide in 40 mL HBr at -10°C bath temperature and the reaction mixture was then warmed to room temperature.
  • the reaction mixture was heated at 55°C for 20 min, cooled and then extracted with ethyl acetate three times.
  • the combined organic layer was washed with water and saturated brine solution, dried over sodium sulfate and concentrated.
  • the crude material was purified by column chromatography (5:95 ethyl acetate: pet ether) to afford solid product.
  • Diazonium salt was portion wise added into the freshly prepared cuprous bromide in 40 mL HBr at -10°C bath temperature and the reaction mixture warmed to room temperature. Then the reaction mixture was heated at 55°C for 20 min, cooled to room temperature and extracted with ethyl acetate three times. The combined organic layer was washed with water and saturated brine solution, dried over sodium sulfate and concentrated. The product was purified by crystallization from DCM/Pet ether.
  • PROTOCOL G Additional examples of analogous ring systems constructed using similar Sandmeyer type strategies
  • PROTOCOL H Pyrazole synthesis via addition of hydrazines to ⁇ -acetylenic ketones
  • PROTOCOL I General procedure for the synthesis of pyrazoles via condensation of hydrazines with ⁇ -diketones:
  • PROTOCOL J Pyrazole synthesis via condensation or hydrazines with ⁇ -Cyanoketones
  • PROTOCOL K chlorination of pyrazoles with NAOCl in glacial Acetic acid
  • PROTOCOL L chlorination or bromination of pyrazoles with N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS):
  • PROTOCOL M General procedure for reduction of Nitropyrazoles
  • PROTOCOL N Functionalization of alkyl substituted heteroaryl ring systems: aminomethylation
  • This intermediate ester (5g, 0.019mol) was taken in CCl 4 (100mL) and AIBN (0.053g, 0.33mmol) was added to it under nitrogen. The mixture was irradiated with a regular light bulb. The mixture was brought to reflux and then NBS (3.42g, 0.019mol), in four portions in 15min intervals, was added to the mixture. After complete addition the mixture was left refluxing under the influence of light for 3h. The reaction mixture was then filtered and the filtrate was washed with water and brine.
  • PROTOCOL O Synthesis of (5-Azidomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-acetic acid:
  • PROTOCOL P (vide infra): Synthesis of 2-(5-Azidomethyl-4-chloro-3-trifluromethyl-pyrazol-1-yl)-1-[4-(4-chlorophenyl)-piperazin-1-yl]-ethanone:
  • PROTOCOL Q Synthesis of 2-(5-Aminometyl-4-chloro-3-trifluromethyl-pyrazol-1-yl)-1-[4-(4-chlorophenyl)-piperazin-1-yl]-ethanone
  • the acidic aqueous phase was basified with 1M NaOH, and was extracted once with ethyl acetate. The final ethyl acetate phase was washed once with brine, dried over Na2S04, filtered, and concentrated to an oil.
  • PROTOCOL R Urea derivatization of aminomethyl functionality on pyrazole ring system.
  • the ester (14.8g, 0.0565 mol) was dissolved in THF (100mL) and a solution of LiOH (6.9g) in water (50mL) was added to it. The mixture was stirred for 10h at room temperature Excess THF was evaporated under reduced pressure and the aqueous layer was washed with ethyl acetate to remove any unhydrolysed material. The aqueous layer was then acidified with 1.5N HCl and extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated to obtain the crude acid. On re-crystallization from ether/pet, priduct was obtained as while: crystals.
  • PROTOCOL P Compounds prepared by HATU mediated coupling:
  • the ethyl acetate phase was then dried over Na2SO4, filtered, and concentrated to a residue in vacuo.
  • the residue was dissolved in a minimum volume of 5M HCl in isopropanol, and was precipitated by diluting the solution with ethyl acetate.
  • PROTOCOL S preparation of chloroacetyl arylpiperazines
  • Protocol S was followed using 1-(4-chloro-phenyl) piperazine, Et 3 N, chloroacetyl chloride and methylene chloride.
  • Protocol S was followed using 1-(4-Chloro-phenyl)-3-(S)-methyl-piperazine, Et 3 N, chloroacetyl chloride and methylene chloride. Column chromatography afforded the title compound.
  • PROTOCOL T K 2 CO 3 mediated coupling reaction of chloroacetyl arylpiperazines with pyrazoles
  • Protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • 13 C NMR 400 MHz, CDCl 3 ): 162, 146.4, 142.2, 118.5, 116.2, 52, 50.4, 46.2, 42.2, 15.2.
  • Protocol T was followed using 3-Heptafluoropropyl-5-methyl-4-nitro-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl)-ethanone and DMF.
  • Protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 4-Bromo-5-methyl-3-trifluoromethyl-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl)-ethanone and DMF.
  • Protocol T was followed using 4-Bromo-5-phenyl-1H-pyrazol-3-ylamine, K 2 CO 3 , 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 4-Chloro-5-methyl-1H-pyrazol-3-ylamine, K 2 CO 3 , 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 4-Chloro-3-trifluoromethyl-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 3-(4-Fluoro-phenyl)-5-methylsulfanyl-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 4-Chloro-3-(4-Fluoro-phenyl)-5 -methylsulfanyl-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 4-Chloro-3-(4-Fluoro-phenyl)-5-methylsulfanyl-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 4-Chloro-3-Thiophen-2-yl-2H-pyrazole-5-carboxylic acid ethyl ester, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • 1 H NMR 400 MHz, CDCl 3 ); 6.92-7.02 (m, 4H), 5.14 (s, 2H), 3.64-3.82 (m, 4H), 3.6 (s, 2H), 3.1-3.22 (m, 4H), 2.16 (s, 3H).
  • 1 H NMR 400 MHz, CDCl 3 ): 7.18-7.24 (m. 2H), 6.78-6.84 (m, 2H).
  • Protocol T was followed using 4-Chloro-5-n-butyl-3-trifluoromethyl-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • 1 H NMR 400 MHz, CDCl 3 ); 7.58-7.62 (d, 1H), 7.52 (s, 1H), 6.95-7.1 (m, 2H), 6.84-6.92 (dd, 2H), 5.00 (s, 2H).
  • Protocol T was followed using 3-Trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • 1 H NMR 400 MHz, CDCl 3 ); 6.95.7.1 (m, 2H), 6.84-6.92 (dd, 2H), 5.00 (s, 2H), 3.62-3.82 (m, 4H), 3.02-3.12 (m, 4H), 2.22-2.32 (d, 6H).
  • Protocol T was followed using 5-Propyl-2H-pyrazole-3-carboxylic acid ethyl ester, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 5-Propyl-2H-pyrazole-3-carboxylic acid ethyl ester, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ ethyl acetate 1/1) afforded the title compound as white solid.
  • Protocol T was followed using 3,5-Bis-trifluoromethyl-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 1H-Pyrazole-3,5-dicarboxylic acid diethyl ester, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 4-Chloro-5-Propyl-2H-pyrazole-3-carboxylic acid ethyl ester, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 5-tert-Butyl-3-trifluoromethyl-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • 1 H NMR 400 MHz, CDCl 3 ): 6.95-7.1 (m, 2H), 6.84-6.92 (dd, 2H), 4.90 (s, 2H), 3.62-3.82 (m, 4H), 3.02-3.12 (m, 4H), 2.24-2.34 (d, 6H).
  • Protocol T was followed using 4-Chloro-3-(5-chloro-thiophen-2-yl)-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 4-Chloro-5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 4-Chloro-5-(5-chloro-thiophen-2-yl)-2H-pyrazole-3-carboxylic acid ethyl ester, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • 1 H NMR 400 MH 2 , CDCl 3 ): 7.18-7.22 (d, 1H), 6.78-6.84 (d, 2H), 4.8 (s, 2H). 4.4 (s, 2H), 3.72-3.82 (m, 4H), 3.08-3.18 (m, 4H), 2.14 (s, 3H).
  • Protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 4-Bromo-5-methyl-1H-pyrazol-3-ylamine, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography ethyl acetate afforded the title compound as a colorless oil.
  • Protocol T was followed using 5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 3,5-Diisopropyl-4-chloro-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • MS (ES) M+H) expected 406.9. found 407.1.
  • 1 H NMR 400 MHz, CDCl 3 ): 7.34-7.38 (m, 1H), 7.24-7.26 (m, 1H), 7.12 (s, 1H).
  • Protocol T was followed using 4-Amino-3-heptafluoropropyl-5-methyl-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 4-Chloro-5-ethyl-3-trifluoromethyl-1-H-pyrazol, K 2 CO 3 , 1-[4-(4-Chloro-3-methoxyphenyl)-piperazine-1-yl]-ethanone and DMF.
  • Protocol T was followed using 4-Chloro-5-isopropyl-3-trifluoromethyl-1-H-pyrazol, K 2 CO 3 , 1-[4-(4-Chloro-3-methoxyphenyl)-piperazine-1-yl]-ethanone and DMF.
  • Protocol T was followed using 4-Chloro-3-isopropyl-5-trifluoromethyl-1-H-pyrazol, K 2 CO 3 , 1-[4-(4-Chloro-3-methoxyphenyl)-piperazine-1-yl]-ethanone and DMF.
  • Protocol T was followed using 4-Chloro-3-n-propyl-5-trifluoromethyl-1-H-pyrazol, K 2 CO 3 , 1-[4-(4-Chloro-3-methoxyphenyl)-piperazine-1-yl]-ethanone and DMF.
  • Protocol T was followed using 4-Bromo-3-phenyl-5-trifluoromethyl-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 4-Chloro-5-phenyl-3-trifluoromethyl-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • 1 H NMR 400 MHz, CDCl 3 ): 7.78-7.84 (m, 2H), 7.36-7.52 (m, 4H).
  • Protocol T was followed using 4-Chloro-3-[3-Fluorophenyl]-5-trifluoromethyl-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • Protocol T was followed using 4-Chloro-5-[3-Fluorophenyl]-3-trifluoromethyl-1H-pyrazole, K 2 CO 3 , 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF.
  • 1 H NMR 400 MHz, CDCl 3 ): 7.64-7.68 (d, 1H), 7.56-7.62 (d, 1H), 7.36-7.42 (m, 1H), 7.22-7.24 (m. 2H), 7.08-7.12 (m, 1H), 6.42-6.52 (m, 2H), 5.2 (s, 2H), 3.9 (s, 3H), 3.62-3.82 (m, 4H), 3.12-3.22 (m, 4H).
  • PROTOCOL U for the K 2 CO 3 mediated coupling reaction of chloroacetyl substituted arylpiperazines with novel heteraryl ring systems
  • Benzimidazole (0.785g, 0.7mmol) was taken in dry DMF (15ml) and dry potassium carbonate (340mg) and KI (20mg) was added to it and the reaction mixture stirred at room temperature for 1h under nitrogen.
  • 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (200mg, 1.1mmol) in DMF (5ml) was then added to the mixture through a syringe. The reaction was then heated at 140°C for 14h, cooled and then quenched with water and extracted with ethyl acetate.
  • 2,4-dimethylimidazole (0.633g, 0.7mmol) was taken up in dry DMF (15ml) and dry potassium carbonate (340mg) and KI (20mg) was added and the reaction mixture was stirred at room temperature for 1h under nitrogen.
  • 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (200mg, 1.1mmol) in DMF (5ml) was then added to the mixture through a syringe. The reaction was then heated at 140°C for 14h, cooled and quenched with water and extracted with ethyl acetate.
  • This compound (90mg, 0.275mmol) was taken into dry CH 2 Cl 2 (10ml) and cooled to 0°C. To this cold mixture was first added 4-chlorophcnyl-piperazine (0.059g, 0.31 mmol) followed by the addition of T3P (0.35g, 0.55mmol, 50% solution in EtOAc). The reaction was left overnight at room temperature. The mixture was diluted with CH 2 Cl 2 , and then washed sequentially with saturated NaHCO3 solution, brine, dried over Na2S04, and concentrated to afford the crude product.
  • This example illustrates the activity associated with representative compounds of the invention.
  • THP-1 cells were obtained from ATCC and cultured as a suspension in RPMI-1640 medium supplemented with 2 mM L-glutamine, 1.5 g/L sodium bicarbonate, 4.5 g/L glucose, 10 mM HEPES, 1 mM sodium pyruvate, 0.05% 2-mercaptoethanol and 10% FBS. Cells were grown under 5% CO 2 /95% air, 100% humidity at 37°C and subcultured twice weekly at 1:5 and harvested at 1 x 10 6 cells/ml. THP-1 cells express CCR1 and can be used in CCR1 binding and functional assays.
  • Monocytes were isolated from human buffy coats using the Miltenyi bead isolation system (Miltenyi, Auburn, CA). Briefly, following a Ficoll gradient separation to isolate peripheral blood mononuclear cells, cells were washed with PBS and the red blood cells lysed using standard procedures. Remaining cells were labeled with anti-CD14 antibodies coupled to magnetic beads (Miltenyi Biotech, Auburn, CA). Labeled cells were passed through AutoMACS (Miltenyi, Auburn, CA) and positive fraction collected. Monocytes express CCR1 and can be used in CCR1 binding and functional assays.
  • Miltenyi bead isolation system Miltenyi, Auburn, CA.
  • CCR1 expressing cells were centrifuged and resuspended in assay buffer (20 mM HEPES pH 7.1, 1.40 mM NaCl, 1 mM CaCl 2 , 5 mM MgCl 2 , and with 0.2% bovine serum albumin) to a concentration of 2.2 x 10 5 cells/ml for THP-1 cells and 1.1 x 10 6 for monocytes.
  • Binding assays were set up as follows. First, 0.09 ml of cells (1 x 10 5 THP-1 cells/well or 5 x 10 5 monocytes) was added to the assay plates containing the compounds, giving a final concentration of ⁇ 2-10 ⁇ M each compound for screening (or part of a dose response for compound IC 50 determinations).
  • Control wells containing either diluent only (for total counts) or excess MIP-1 ⁇ or MIP-1 ⁇ (1 ⁇ g/ml, for non-specific binding) were used to calculate the percent of total inhibition for compound.
  • the computer program Prism from GraphPad, Inc. (San Diego, Ca) was used to calculate IC 50 values. IC 50 values are those concentrations required to reduce the binding of labeled MIP-1 ⁇ to the receptor by 50%.
  • THP-1 or monocytes were incubated with 3 ⁇ M of INDO-1AM dye (Molecular Probes; Eugene, OR) in cell media for 45 minutes at room temperature and washed with phosphate buffered saline (PBS). After INDO-1AM loading, the cells were resuspended in flux buffer (Hank's balanced salt solution (HBSS) and 1% FBS). Calcium mobilization was measured using a Photon Technology International spectrophotometer (Photon Technology International; New Jersey) with excitation at 350 nm and dual simultaneous recording of fluorescence emission at 400 nm and 490 nm. Relative intracellular calcium levels were expressed as the 400 nm/490 nm emission ratio.
  • INDO-1AM dye Molecular Probes; Eugene, OR
  • chemokine ligands may be used over a range from 1 to 100 nM. The emission ratio was plotted over time (typically 2-3 minutes).
  • Candidate ligand blocking compounds up to 10 ⁇ M were added at 10 seconds, followed by chemokines at 60 seconds (i.e., MIP-1 ⁇ ; R&D Systems; Minneapolis, MN) and control chemokine (i.e., SDF-1 ⁇ ; R&D Systems; Minneapolis, MN) at 150 seconds.
  • Chemotaxis assays were performed using 5 ⁇ m pore polycarbonate, polyvinylpyrrolidone-coated filters in 96-well chemotaxis chambers (Neuroprobe; Gaithersburg, MD) using chemotaxis buffer (Hank's balanced salt solution (HBSS) and 1% FBS).
  • CCR1 chemokine ligands i.e, MIP-1 ⁇ , Leukotactin; R&D Systems; Minneapolis, MN
  • Other chemokines i.e., SDF-1 ⁇ , R&D Systems; Minneapolis, MN are used as specificity controls.
  • the lower chamber was loaded with 29 ⁇ l of chemokine (i.e., 0.1 nM MIP-1 ⁇ ) and varying amounts of compound; the top chamber contained 100,000 THP-1 or monocyte cells in 20 ⁇ l.
  • the chambers were incubated 1-2 hours at 37°C, and the number of cells in the lower chamber quantified either by direct cell counts in five high powered fields per well or by the CyQuant assay (Molecular Probes), a fluorescent dye method that measures nucleic acid content and microscopic observation.
  • radioactive ligand i.e, MIP-1 ⁇ or leukotactin binding to cells expressing CCR1 on the cell surface (for example, THP-1 cells or isolated human monocytes).
  • MIP-1 ⁇ or leukotactin binding to cells expressing CCR1 on the cell surface
  • CCX-105 was identified from the compound screening effort.
  • inhibitory activity was titered over a 1 x 10 -10 to 1 x 10 -4 M range of compound concentrations. In the assay, the amount of compound was varied; while cell number and ligand concentration were held constant. Compound CCX-105 was titered and found to be a potent inhibitor of CCR I specific chemokine binding (see Table, for compound 1.001).
  • CCR1 is a seven transmembrane, G-protein linked receptor.
  • a hallmark of signaling cascades induced by the ligation of some such receptors is the pulse-like release of calcium ions from intracellular stores.
  • Calcium mobilization assays were performed to determine if the candidate CCR1 inhibitory compounds were able to also block aspects of CCR1 signaling.
  • Candidate compounds able to inhibit ligand binding and signaling with an enhanced specificity over other chemokine and non-chemokine receptors were desired.
  • CCR1 chemokine ligands i.e., MIP-1 ⁇ , MPIF-1, Leukotactin, etc.
  • CCR1 chemokine ligands i.e., MIP-1 ⁇ , MPIF-1, Leukotactin, etc.
  • THP-1 cells or monocytes were loaded with INDO-1/AM and assayed for calcium release in response to CCR1 chemokine ligand (i.e., MIP-1 ⁇ ) addition.
  • non-CCR1 ligands, specifically bradykinin was added, which also signals via a seven transmembrane receptor. Without compound, a pulse of fluorescent signal will be seen upon MIP-1 ⁇ addition.
  • CCX-105 was able to significantly and specifically inhibit signaling from CCR1.
  • Table 2 Inhibition of calcium signaling Compound MIP-1 ⁇ 1 Bradykinin 1
  • chemokines One of the primary functions of chemokines is their ability to mediate the migration of chemokine receptor-expressing cells, such as white blood cells.
  • chemokine receptor-expressing cells such as white blood cells.
  • a chemotaxis assay was employed. THP-1 myelomonocytic leukemia cells, which resemble monocytes, as wells as freshly isolated monocytes, were used as targets for chemoattraction by CCR1 chemokine ligands (i.e., MIP-1 ⁇ , CCL15/leukotactin).
  • IC 50 values are those compound concentrations required to inhibit the number of cells responding to a CCR1 agonist by 50%.
  • LPS bacterial membrane component lipopolysaccharide
  • CCX-105 was able to significantly and specifically inhibit the inflammatory response in this in vivo assay. Table 3. CCX-105 efficacy in a rabbit model of destructive joint inflammation synovium inflammation score Vehicle 3 CCX-105 (dose 1) 2 CCX-105 (dose 2) 1
  • Rat collagen arthritis is an experimental model of polyarthritis that has been widely used for preclinical testing of numerous anti-arthritic agents (see Trentharn, et al., J. Exp. Med. 146(3):857-868 (1977 ), Bendele, et al., Toxicologic Pathol. 27:134-142 (1999 ), Bendele, et al., Arthritis Rheum. 42:498-506 (1999 ))
  • the hallmarks of this model are reliable onset and progression of robust, easily measurable polyarticular inflammation, marked cartilage destruction in association with pannus formation and mild to moderate bone resorption and periosteal bone proliferation.
  • Female Lewis rats (approximately 0.2 kilograms) were anesthetized with isoflurane and injected with Freund's Incomplete Adjuvant containing 2 mg/ml bovine type II collagen at the base of the tail and two sites on the back on days 0 sand 6 of this 17 day study.
  • Compound 1.028 was dosed daily in a sub-cutaneous manner from day 0 till day 17 at a dose of 25 mg/kg and a volume of 1 ml/kg in the following vehicle (20% N,N-dimethylacetamide, 75% corn oil, 5% Tween-80). Caliper measurements of the ankle joint diameter were taken, and reducing joint swelling was taken as a measure of efficacy.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pulmonology (AREA)
  • Cardiology (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Claims (38)

  1. Verwendung einer Verbindung mit der Formel
    Figure imgb0389
     oder eines pharmazeutisch verträglichen Salzes davon, worin
    der Index n eine ganze Zahl von 1 bis 2 ist;
    der Index m eine ganze Zahl von 0 bis 10 ist;
    jedes R1 ein Substituent ist, unabhängig ausgewählt ist aus der Gruppe, bestehend aus C1-8-Alkyl, C1-8-Haloalkyl, C3-6-Cycloalkyl, C2-8-Alkenyl und
    C2-8-Alkinyl, -CORa, -CO2Ra, -CONRaRb, -NRaCORb, -SO2Ra, -X1CORa, -X1CO2Ra X1CONRaRb, -X1NRaCORb, -X1SO2Ra, -X1SO2NRaRb -X1NRaRb, -X1ORa, worin X1 ein Element ist, ausgewählt aus der Gruppe, bestehend aus C1-4-Alkylen, C2-4-Alkenylen und C2-4-Alkinylen und jedes Ra und Rb unabhängig ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, C1-8-Alkyl, C1-8-Haloalkyl und C3-6-Cyloalkyl, und worin die aliphatischen Teile von jedem der R1-Substituenten optional substituiert sind mit von einem bis drei Elementen, ausgewählt aus der Gruppe, bestehend aus OH, O(C1-8-Alkyl), SH, S(C1-8-Alkyl), CN, NO2, NH2, NH(C1-8-Alkyl) und N(C1-8-Alkyl)2; Ar1 Phenyl ist, substituiert mit von einem bis drei R2-Substituenten, unabhängig ausgewählt aus der Gruppe, bestehend aus Halogen, -ORc, -OC(O)Rc, -NRcRd, -SRc, -Re, -CN, -NO2, -CO2Rc, -CONRcRd, C(O)Rc, -OC(O)NRcRd, -NRdC(O)Rc, -NRdC(O)2Re, -NRc-C(O)NRcRd, -S(O)Re, -S(O)2Re, -NRcS(O)2Re, -S(O)2NRcRd und -N3 worin jedes Rc und Rd unabhängig ausgewählt ist aus Wasserstoff, C1-8-Alkyl, C1-8-Haloalkyl, C3-6-Cycloalkyl, C2-8-Alkenyl und C2-8-Alkinyl und jedes Re unabhängig ausgewählt ist aus der Gruppe, bestehend aus C1-8-Alkyl, C1-8-Haloalkyl, C3-6-Cycloalkyl, C2-8-Alkenyl und C2-8-Alkinyl und worin der aliphatische Teil von Rc, Rd und Re optional weiter substituiert ist mit von einem bis drei Elementen, ausgewählt aus der Gruppe, bestehend aus OH, O(C1-8-Alkyl), SH, S(C1-8-Alkyl), CN, NO2, NH2, NH(C1-8-Alkyl) und N(C1-8-Alkyl)2; HAr eine Heteroarylgruppe ist, ausgewählt aus der Gruppe, bestehend aus Pyrazolyl und Benzopyrazolyl, und gebunden ist an den Rest des Moleküls über ein Stickstoffatom des Pyrazolylrings bzw. über ein Stickstoffatom des Pyrazolteils des fusionierten Ringsystems, wobei jedes davon optional substituiert ist mit von einem bis fünf R3-Substituenten, unabhängig ausgewählt aus der Gruppe, bestehend aus Halogen, Phenyl, Thienyl, Furanyl, Pyridyl, Pyrimidinyl, Pyrazinyl, Pyridizinyl, Pyrazolyl, Imidazolyl, Thiazolyl, Oxazolyl, Isoxazolyl, Isothiazolyl, Triazolyl, Tetrazolyl, Oxadiazolyl, -ORf, -OC(O)Rf, -NRfRg, -SRf, -Rh, -CN, -NO2, -CO2Rf, -CONRfRg, -C(O)Rf, -OC(O)NRfRg, -NRgC(O)Rf, -NRgC(O)2Rh, -NRf-C(O)NRfRg, -NH-C(NH2)=NH, -NRhC(NH2)=NH, -NH-C(NH2)=NRh, -NH-C/NHRh)=NH, -S(O)Rh, -S(O)2Rh, -NRfS(O)2Rh, -S(O)2NRfRg, -NRfS(O)2Rh, -NRfS(O)2NRfRg, -N3, -X3ORf, - XIOC(O)Rf, -X3NRfRg, -X3SRf, -X3CN, -X3NO2, -X3CO2Rf, -X3CONRfRg, - X3C(O)Rf, -X3OC(O)NRfRg, -X3NRgC(O)Rf, -X3NRgC(O)2Rh, -X3NRf-C(O)NRfR9, -X3NH-C(NH2)=NH, -X3NRhC(NH2)=NH, -X3NH-C(NH2)=NR , -X3NH-C(NHRh)=NH, -X3S(O)Rh, -X3S(O)2Rh, -X3NRfS(O)2Rh, -X3S(O)2NRfRg und -X3N3 worin X3 ausgewählt ist aus der Gruppe, bestehend aus C1-4-Alkylen, C2-4-Alkenylen und C2-4-Alkinylen und jedes Rf und Rg unabhängig ausgewählt ist aus Wasserstoff, C1-8-Alkyl, C1-8-Haloalkyl, C3-6-Cycloalkyl, C2-8-Alkenyl, C2-8-Alkinyl, Aryl, Heteroaryl, Aryl-C1-4-Alkyl und Aryloxy-C1-4-Alkyl und jedes Rh unabhängig ausgewählt ist aus der Gruppe, bestehend aus C1-8-Alkyl, C1-8-Haloalkoyl, C3-6-Cycloalkyl, C2-8-Alkenyl, C2-8-Alkinyl, Aryl, Heteroaryl, Aryl-C1-4-Alkyl und Aryloxy-C1-4-Alkyl, worin die aliphatischen Teile von Rf, Rg und Rh optional weiter substituiert sind mit von einem bis drei Mitgliedern, ausgewählt aus der Gruppe, bestehend aus OH, O(C1-8-Alkyl), SH, S(C1-8-Alkyl), CN, NO2, NH2, NH(C1-8-Alkyl) und N(C1-8-Alkyl)2; und worin jede Phenyl-, Thienyl-, Furanyl-, Pyridyl-, Pyrimidinyl-, Pyrazinyl-, Pyridizinyl-, Pyrazolyl-, Imidazolyl-, Thiazolyl-, Oxazolyl-, Isoxazolyl-, Isothiazolyl-, Triazolyl-, Tetrazolyl- oder Oxadiazolyl-Gruppe, die vorliegt, optional substituiert ist mit von einem bis drei Substituenten, ausgewählt aus der Gruppe, bestehend aus Halogen, -ORf, -NRfRg, --Rh, -CN, -NO2, -CO2Rf, -CONRfRg, -C(O)Rf, -X3ORf, -X3NRfRg, -X3NRfS(O)2Rh und -X3S(O)2NRfRg, L1 -CH2- ist und optional substituiert ist mit Phenyl, -Rk, -X4ORi, -X4OC(O)Ri, -X4NRiRj, -X4RSi, -X4CN oder -X4NO2, worin X4 ausgewählt ist aus der Gruppe, bestehend aus C-1-4-Alkylen, C2-4-Alkenylen und C2-4-Alkinylen und jedes Ri und Rj unabhängig ausgewählt ist aus Wasserstoff, C-1-8-Alkyl, C-1-8-Haloalkyl, C3-6-Cycloalkyl, C2-8-Alkenyl, C2-8-Alkinyl, Aryl, Heteroaryl, Aryl-C-1-4-Alkyl und Aryloxy-C-1-4-Alkyl und jedes Rk unabhängig ausgewählt ist aus der Gruppe, bestehend aus C1-8-Alkyl, C1-8-Haloalkyl, C3-6-Cycloalkyl, C2-8-Alkenyl, C2-8-Alkinyl, Aryl, Heteroaryl, Aryl-C-1-4-Alkyl und Aryloxy-C-1-4-Alkyl, bei der Herstellung eines Medikaments zur Verwendung in einem Verfahren zur Behandlung von CCR1-vermittelten Krankheiten oder Zuständen, umfassend das Verabreichen an ein Subjekt, das eine therapeutisch wirkungsvolle Menge der Verbindung erfordert.
  2. Verwendung nach Anspruch 1, worin HAr Pyrazolyl ist, das optional substituiert ist mit von ein bis drei R3-Gruppen, unabhängig ausgewählt aus der Gruppe, bestehend aus Halogen, Phenyl, Thienyl, -ORf, -OC(O)Rf, -NRfRg, -SRf, -Rh, -CN, -NO2, -CO2Rf, -CONRfRg, -C(O)Rf, -OC(O)NRf,Rg, -NRgC(O)Rf, -NRgC(O)2Rh, -NRf-C(O)NRfRg, -S(O)Rh, -S(O)2Rh, -S(O)2NRfRg, -NRfS(O)2Rh, -NRfS(O)2NRfRg, -N3, -X3ORf, -X3OC(O)Rf, -X3NRfRg, -X3SRf, -X3CN, X3NO2, -X3CO2Rf, -X3CONRfRg, -X3C(O)Rf, -X3OC(O)NRfRg, -X3NRgC(O)Rf-, X3NRgC(O)2Rh, -X3NRf-C(O)NRfRg, -X3S(O)Rh, -X3S(O)2Rh, -X3NRfS(O)2Rh, -X3S(O)2NRfR9 und -X3N3, worin Rf und Rg jeweils unabhängig ausgewählt sind aus der Gruppe, bestehend aus H, C1-8-Alkyl und C1-8-Haloalkyl und jedes Rh unabhängig ausgewählt ist aus der Gruppe, bestehend aus C1-8-Alkyl und C1-8-Haloalkyl.
  3. Verwendung nach Anspruch 2, worin n 1 ist, m 0-2 ist, HAr Pyrazolyl ist, das substituiert ist mit drei R3-Gruppen und L1 -CH2 ist.
  4. Verwendung nach Anspruch 3, worin Ar1 ausgewählt ist aus der Gruppe, bestehend aus der Gruppe
    Figure imgb0390
    Figure imgb0391
    Figure imgb0392
    Figure imgb0393
    Figure imgb0394
    Figure imgb0395
    Figure imgb0396
    Figure imgb0397
  5. Verwendung nach Anspruch 1, worin die Verbindung die Formel:
    Figure imgb0398
     aufweist oder eines pharmazeutisch verträglichen Salzes davon, worin jedes von R1a, R1b, R1c, R1d, R1e, R1f, R1g und R1h ein Element darstellt, unabhängig ausgewählt aus der Gruppe, bestehend aus H, C1-8-Alkyl, C1-8-Haloalkyl, C3-6-Cycloalkyl, C2-8-Alkenyl und C2-8-Alkinyl.
  6. Verwendung nach Anspruch 5, worin die ein bis drei R2-Substituenten unabhängig ausgewählt sind aus der Gruppe, bestehend aus Halogen, -ORc, -OC(O)Rc, -NRcRd, -SRc, -Re, -CN, -NO2, -CO2Rc, -CONRcR d, -C(O)Rc, -OC(O)NRcRd, -NRdC(O)Rc, -NRdC(O)2Re, -NRc-C(O)NRcRd, -S(O)Re, -S(O)2Re, -NRcS(O)2NRcRd und -N3, worin jedes Rc und Rd unabhängig ausgewählt ist aus Wasserstoff, C1-8-Alkyl, C1-8-Haloalkyl, C3-6-Cycloalkyl, C2-8-Alkenyl und C2-8-Alkinyl und jedes Re unabhängig ausgewählt ist aus der Gruppe, bestehend aus C1-8-Alkyl, C1-8-Haloalkyl, C3-6-Cycloalkyl, C2-8-Alkenyl und C2-8-Alkinyl.
  7. Verwendung nach Anspruch 6, worin L1 -CH2- ist, optional substituiert mit einem oder mehreren Substituenten, unabhängig ausgewählt aus der Gruppe, bestehend aus C1-4-Alkyl, C-1-4-Haloalkyl und Phenyl.
  8. Verwendung nach Anspruch 7, worin die eine bis fünf R3-Gruppen unabhängig ausgewählt sind aus der Gruppe, bestehend aus Halogen, Phenyl, Thienyl, -ORf, -OC(O)Rf, -NRfR9, -SRf, -Rh, -CN, -NO2, -CO2Rf, -CONRfRg, -C(O)Rf, -OC(O)NRfR9, -NRgC(O)Rf, -NRgC(O)2Rh, -NRf-C(O)NRfRg, -S(O)Rh, -S(O)2Rh, -S(O)2Rh, -S(O)2NRfRg, -NRfS(O)2Rh, -NRfS(O)2NRfRg, -X3ORf, -X3OC(O)Rf, -X3NRfRg, -X3SRf, -X3CN, -X3NO2, -X3CO2Rf, -X3CONRfRg, -X3C(O)Rf, -X3OC(O)NRfRg, -X3NRgC(O)Rf, -X3NRgC(O)Rh, -X3NRf-C(O)NRfRg, -X3S(O)Rh, -X3S(O)2Rh, -X3NRfS(O)2Rh und -X3S(O)2NRfRg, worin X3 ausgewählt ist aus der Gruppe, bestehend aus C1-4-Alkylen, C2-4-Alkenylen und C2-4-Alkinylen, und jedes Rf und Rg unabhängig ausgewählt ist aus Wasserstoff, C1-8-Alkyl, C1-8-Haloalkyl, C3-6-Cycloalkyl, C2-8-Alkenyl und C2-8-Alkinyl und jedes Rh unabhängig ausgewählt ist aus der Gruppe, bestehend aus C1-8-Alkyl, C1-8-Haloalkyl, C3-6-Cycloalkyl, C2-8-Alkenyl, C2-8-Alkinyl und worin jede vorliegende Phenyl- oder Thienylgruppe, optional substituiert ist mit von einem bis drei Substituenten, ausgewählt aus der Gruppe, bestehend aus Halogen, -ORf, -NRfRg, -Rh, -CN, -NO2, -CO2Rf, -CONRfRg, -C(O)Rf, -X3ORf, -X3NRfRg, -X3NRfS(O)2Rh und -X3S(O)2NRfRg.
  9. Verwendung nach Anspruch 8, worin HAr optional substituiert ist mit von einer bis drei R3-Gruppen, unabhängig ausgewählt aus der Gruppe, bestehend aus Halogen, Phenyl, Thienyl, -ORf, -CO2Rf, -CORf, -CONRfRg, -NO2, -Rh, -CN, -SRf, -S(O)Rh, -S(O)2Rh und -NRfRg, worin jedes Rf und Rg unabhängig ausgewählt ist aus der Gruppe, bestehend aus H, C1-8-Alkyl und C1-8-Haloalkyl und jedes Rh unabhängig ausgewählt ist aus der Gruppe, bestehend aus C1-8-Alkyl und C1-8-Haloalkyl.
  10. Verwendung nach Anspruch 9, worin HAr ausgewählt ist aus der Gruppe, bestehend aus
    Figure imgb0399
    Figure imgb0400
    Figure imgb0401
    Figure imgb0402
    Figure imgb0403
    Figure imgb0404
  11. Verwendung nach Anspruch 8, worin HAr ausgewählt ist aus der Gruppe, bestehend aus
    Figure imgb0405
    Figure imgb0406
    Figure imgb0407
    Figure imgb0408
    Figure imgb0409
    Figure imgb0410
  12. Verwendung nach Anspruch 9, worin L1 -CH2- ist.
  13. Verwendung nach Anspruch 5, worin Ar1 Phenyl ist, optional substituiert mit einem bis drei R2-Substituenten, unabhängig ausgewählt aus der Gruppe, bestehend aus Halogen, -ORc, OC(O)Rc, -NRcRd, -SRc, -Re, - CN,
    -NO2, -CO2Rc, -CONRcRd, -C(O)Rc, -OC(O)NRcRd, -NRdC(O)Rc,
    -NRdC(O)2Re, -NRc-C(O)NRcRd, -S(O)Re, -S(O)2Re, -S(O)2NRcRd und -N3, worin jedes Rc und Rd unabhängig ausgewählt ist aus Wasserstoff, C1-8-Alkyl, C1-8-Haloalkyl, C3-6-Cycloalkyl, C2-8-Alkenyl und C2-8-Alkinyl und jedes Re unabhängig ausgewählt ist aus der Gruppe, bestehend aus C1-8-Alkyl, C1-8-Haloalkyl, C3-6-Cycloalkyl, C2-8-Alkenyl und C2-8-Alkinyl, worin die Alkylteile der Substituenten optional substituiert sind mit einer oder zwei Hydroxy- oder Aminogruppen; L1 -CH2- ist; HAr Pyrazolyl oder Benzopyrazolyl ist, jedes davon optional substituiert ist mit von einer bis drei R3-Gruppen, unabhängig ausgewählt aus der Gruppe, bestehend aus Halogen, Phenyl, Thienyl, ORf, CO2Rf, CONRfRg, NO2, Rh, CN, SRf, S(O)Rh, S(O)2Rh und NRfRg, worin jedes Rf und Rg unabhängig ausgewählt ist aus der Gruppe, bestehend aus H, C1-8-Alkyl und C1-8-Haloalkyl, und jedes Rh unabhängig ausgewählt ist aus der Gruppe, bestehend aus C1-8-Alkyl und C1-8-Haloalkyl; und jedes R1a, R1b, R1c, R1d, R1e, R1f R1g und R1h Elemente sind, unabhängig ausgewählt aus der Gruppe, bestehend aus H, C-1-4-Alkyl und C-1-4-Haloalkyl, worin mindestens sechs aus R1a bis R1h H sind.
  14. Verwendung nach Anspruch 1, worin die Verbindung die Formel
    Figure imgb0411
     aufweist, worin der Index m eine ganze Zahl von 0 bis 2 ist;
    jedes R1 ein Element ist, ausgewählt aus der Gruppe, bestehend aus C1-4-Alkyl und C1-4-Haloalkyl; R2a, R2b, R2c, R2d und R2e Elemente sind, unabhängig ausgewählt aus der Gruppe, bestehend aus Wasserstoff, Halogen, -ORc, -OC(O)Rc, -NRcRd, -SRc, -Re, -CN, NO2, -CO2Rc, -CONRcRd, -C(O)RC, -OC(O)NRcRd, -NRdC(O)Rc, -NRdC(O)2Re, -NRc-C(O)NRcRd, -S(O)Re, -S(O)2Re, -NRcS(O)2Re, -S(O)2NRcRd und -N3, worin jedes Rc und Rd unabhängig ausgewählt ist aus Wasserstoff, C1-8-Alkyl, C1-8-Halolalkyl, C3-6-Cycloalkyl, C2-8-Alkenyl und C2-8-Alkinyl und jedes Re unabhängig ausgewählt ist aus der Gruppe, bestehend aus C1-8-Alkyl, C1-8-Haloalkyl, C3-6-Cycloalkyl, C2-8-Alkenyl und C2-8-Alkinyl und jedes Rc, Rd und Re optional weiter substituiert ist mit von einem bis drei Elementen, ausgewählt aus der Gruppe, bestehend aus OH, O(C1-8-Alkyl), SH, S(C1-8-Alkyl), CN, NO2, NH2, NH(C1-8-Alkyl) und N(C1-8-Alkyl)2; R3a, R3b und R3c jeweils Mitglieder sind, unabhängig ausgewählt aus der Gruppe, bestehend aus Wasserstoff, Halogen, Phenyl, Thienyl, -ORf, -OC(O)RF, -NRfR9, -SRf, -Rh, -CN, -NO2, -CO2Rf, -CONRfRg, -C(O)Rf, - OC(O)NRfRg, -NRgC(O)Rf, -NRgC(O)2Rh, -NRfC(O)NRfRg, -S(O)Rh, -S(O)2Rh, -NRfS(O)2Rh, -S(O)2NRfRg, -NRfS(O)2Rh, -NRfS(O)2NRfRg, -X3ORf, -X3OC(O)Rf, -X3NRfRg, -X3SRf, -X3CN, -X3NO2, -X3CO2Rf, -X3CONRfRg, -X3C(O)Rf, -X3C(O)Rf, -X3OC(O)NRfRg, -X3NR9C(O)Rf, -X3NRgC(O)2Rh, -X3NRf-C(O)NRfRg, -X3S(O)Rh, -X3S(O)2Rh, -X3NRfS(O)2Rh und X3S(O)2NRfRg, worin X3 C1-4-Alkylen ist, jedes Rf und Rg unabhängig ausgewählt ist aus Wasserstoff, C1-8-Alkyl, C1-8-Haloalkyl, C3-6-Cycloalkyl, C2-8-Alkenyl und C2-8-Alkinyl, und jedes Rh unabhängig ausgewählt ist aus der Gruppe, bestehend aus C1-8-Alkyl, C1-8-Haloalkyl, C3-6-Cycloalkyl, C2-8-Alkenyl und C2-8-Alkinyl und worin jede vorliegende Phenyl- oder Thienylgruppe optional substituiert ist mit von einem bis drei Substituenten, ausgewählt aus der Gruppe, bestehend aus Halogen, -ORf, -NRfRg, -Rh, -CN, -NO2, -CO2Rf, -CONRfRg, -C(O)Rf, -X3NRfRg, -X3NRfS(O)2Rh und -X3S(O)2NRfRg.
  15. Verwendung nach Anspruch 14, worin m 0 oder 1 ist und mindestens eines von R2a und R2e Wasserstoff ist.
  16. Verwendung nach Anspruch 15, worin mindestens eines von R3a, R3b und R3c ausgewählt ist aus der Gruppe, bestehend aus Halogen und C-1-4-Haloalkyl.
  17. Verwendung nach Anspruch 16, worin R2d Wasserstoff ist und mindestens zwei von R3a, R3b und R3c ausgewählt sind aus der Gruppe, bestehend aus Halogen und C-1-4-Haloalkyl.
  18. Verwendung nach Anspruch 17, worin R2c ausgewählt ist aus der Gruppe, bestehend aus F, Cl, Br, CN, NO2, CO2CH3, C(O)CH3 und S(O)2CH3 und jedes von R3a, R3b und Rc von Wasserstoff verschieden ist.
  19. Verwendung nach Anspruch 14, worin m 0 oder 1 ist und R2a und R2e jeweils Wasserstoff sind.
  20. Verwendung nach Anspruch 19, worin mindestens eines von R3a, R3b und R3c ausgewählt ist aus der Gruppe, bestehend aus Halogen und C1-4-Haloalkyl.
  21. Verwendung nach Anspruch 20, worin jedes von R3a, R3b und R3c von Wasserstoff verschieden ist.
  22. Verwendung nach Anspruch 14, worin m 0 oder 1 ist und R2b und R2e jeweils Wasserstoff sind.
  23. Verwendung nach Anspruch 14, worin die Verbindung die Formel
    Figure imgb0412
     aufweist.
  24. Verwendung nach Anspruch 23, worin R3c und R3a jeweils unabhängig ausgewählt sind aus der Gruppe, bestehend aus C1-6-Alkyl, C1-6-Haloalkyl und C3-6-Cycloalkyl.
  25. Verwendung nach Anspruch 14, worin die Verbindung die Formel
    Figure imgb0413
     aufweist, worin R2c Halogen, Cyano oder Nitro ist; R2b Re oder -ORc ist; R3a ausgewählt ist aus der Gruppe, bestehend aus NH2, CF3, SCH3, Ph und Thienyl; R3b Chlor oder Brom ist; und R3c ausgewählt ist aus der Gruppe, bestehend aus C1-6-Alkyl, C1-6-Haloalkyl und C3-6-Ccyloalkyl.
  26. Verwendung nach Anspruch 14, worin die Verbindung die Formel
    Figure imgb0414
     aufweist, worin R2c Halogen, Cyano oder Nitro ist; R2b Re oder ORc ist; R3a ausgewählt ist aus der Gruppe, bestehend aus C1-6-Alkyl, C1-6-Haloalkyl und C3-6-Cycloalkyl; R3c ausgewählt ist aus der Gruppe, bestehend aus NH2, CF3, SCH3, Ph und Thienyl; und R3b Chlor oder Brom ist.
  27. Verwendung nach Anspruch 14, worin die Verbindung die Formel
    Figure imgb0415
     aufweist, worin R2a von Wasserstoff verschieden ist; R2c Halogen, Cyano oder Nitro ist; R2d Re oder -ORc ist; R3a ausgewählt ist aus der Gruppe, bestehend aus C1-6-Alkyl, C1-6-Haloalkyl und C3-6-Cycloalkyl; R3b Chlor oder Brom ist; und R3c ausgewählt ist aus der Gruppe, bestehend aus NH2, CF3, SCH3, Ph und Thienyl.
  28. Verwendung nach Anspruch 14, worin die Verbindung die Formel
    Figure imgb0416
     aufweist, worin R2a verschieden von Wasserstoff ist; R2c Halogen, Cyano oder Nitro ist; R2d Re oder -ORc ist; R3a ausgewählt ist aus der Gruppe, bestehend aus NH2, CF3, SCH3, Ph und Thienyl; R3b Chlor oder Brom ist; und R3c ausgewählt ist aus der Gruppe, bestehend aus C1-6-Alkyl, C1-6-Haloalkyl und C3-6-Cycloalkyl.
  29. Verwendung nach Anspruch 22, worin mindestens eines von R3a, R3b und R3c ausgewählt ist aus der Gruppe, bestehend aus Halogen und C1-4-Halolalkyl.
  30. Verwendung nach Anspruch 29, worin jedes von R3a, R3b und R3c verschieden von Wasserstoff ist.
  31. Verwendung nach einem der Ansprüche 1 bis 30, worin CCR1-vermittelte Krankheit oder Zustand ein Entzündungszustand ist.
  32. Verwendung nach einem der Ansprüche 1 bis 30, worin die CCR1-vermittelte Krankheit oder der CC1-vermittelte Zustand eine Immunregulationsstörung ist.
  33. Verwendung nach einem der Ansprüche 1 bis 30, worin die CCR1-vermittelte Krankheit oder der CCR1-vermittelte Zustand ausgewählt ist aus der Gruppe, bestehend aus rheumatischer Arthritis, Multiple Sklerose, Transplantatabstoßung, Dermatitis, Ekzem, Urtikaria, Vasculitis, entzündliche Darmerkrankung, Lebensmittelallergie und Enzephalomyelitis.
  34. Verwendung nach einem der Ansprüche 1 bis 30, worin die Verabreichung oral, parenteral, rektal, transdermal, sublingual, nasal oder topisch ist.
  35. Verwendung nach einem der Ansprüche 1 bis 30, worin die Verbindung in Kombination mit einem entzündungshemmenden oder analgetischen Mittel verwendet wird.
  36. Verbindung nach einem der Ansprüche 1 bis 30 zur Verwendung in einem Verfahren zur Behandlung von CCR1-vermittelten Krankheiten oder Zuständen, wie in einem der Ansprüche 1 und 31 bis 35 definiert.
  37. Pharmazeutische Zusammensetzung, umfassend einen pharmazeutsch verträglichen Exzipienten und eine Verbindung nach einem der Ansprüche 1 bis 30 mit der Maßgabe, dass die Verbindung verschieden ist von CAS Reg. Nr. 492422-98-7, 1-[[4-Brom-5-methyl-3-(trifluormethyl)-1 H-pyrazol-1-yl]acetyl]-4-(5-chlor-2-methylphenyl)piperazin; CAS Reg. Nr. 351986-92-0, 1-[[4-Chlor-5-methyl-3-(trilfuormethyl)-1 H-pyrazol-1-yl]acetyl]-4-(4-fluorphenyl)-piperazin oder CAS Reg. Nr. 356039-23-1, 1-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)acetyl]-4-(4-fluorphenyl)-piperazin.
  38. Verbindung nach einem der Ansprüche 1 bis 30, mit der Maßgabe, dass die Verbindung verschieden ist von CAS Reg. Nr. 492422-98-7, 1-[[4-Brom-5-methyl-3-(trifluormethyl)-1 H-pyrazol-1-yl]acetyl]-4-(5-chlor-2-methylphenyl)piperazin; CAS Reg. Nr. 351986-92-0, 1-[[4-Chlor-5-methyl-3-(trifluormethyl)-1 H-pyrazol-1-yl]acetyl]-4-(4-fluorphenyl)-piperazin oder CAS Reg. Nr. 356039-23-1, 1-[(3,5-Dimethyl-4-nitro-1H-pyrazol-1-yl)acetyl]-4-(4-fluorphenyl)-piperazin.
EP03737057A 2002-06-12 2003-06-11 1-aryl-4-substituierte piperazin-derivate zur verwendung als ccr1-antagonisten zur behandlung von entzündungen und immunerkrankungen Expired - Lifetime EP1531822B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US45371102P 2002-06-12 2002-06-12
US453711P 2002-06-12
PCT/US2003/018660 WO2003105853A1 (en) 2002-06-12 2003-06-11 1-aryl-4-substituted piperazines derivatives for use as ccr1 antagonists for the treatment of inflammation and immune disorders

Publications (2)

Publication Number Publication Date
EP1531822A1 EP1531822A1 (de) 2005-05-25
EP1531822B1 true EP1531822B1 (de) 2009-08-05

Family

ID=29736828

Family Applications (1)

Application Number Title Priority Date Filing Date
EP03737057A Expired - Lifetime EP1531822B1 (de) 2002-06-12 2003-06-11 1-aryl-4-substituierte piperazin-derivate zur verwendung als ccr1-antagonisten zur behandlung von entzündungen und immunerkrankungen

Country Status (14)

Country Link
US (2) US7157464B2 (de)
EP (1) EP1531822B1 (de)
JP (1) JP4723242B2 (de)
KR (1) KR101255356B1 (de)
CN (1) CN1867336B (de)
AT (1) ATE438401T1 (de)
AU (1) AU2003236500B9 (de)
CA (1) CA2488202C (de)
DE (1) DE60328690D1 (de)
DK (1) DK1531822T3 (de)
ES (1) ES2329356T3 (de)
HK (1) HK1099206A1 (de)
MX (1) MXPA04012393A (de)
WO (1) WO2003105853A1 (de)

Families Citing this family (63)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4723242B2 (ja) * 2002-06-12 2011-07-13 ケモセントリックス インコーポレーティッド 炎症および免疫障害治療用ｃｃｒ１アンタゴニストとして使用するための１−アリール−４−置換ピペラジン誘導体
US7589199B2 (en) 2002-06-12 2009-09-15 Chemocentryx, Inc. Substituted piperazines
US20050256130A1 (en) * 2002-06-12 2005-11-17 Chemocentryx, Inc. Substituted piperazines
US7842693B2 (en) * 2002-06-12 2010-11-30 Chemocentryx, Inc. Substituted piperazines
US8013156B2 (en) * 2003-03-19 2011-09-06 Exelixis, Inc. Tie-2 modulators and methods of use
US7754711B2 (en) * 2003-07-30 2010-07-13 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
AU2011265309B2 (en) * 2003-11-21 2014-06-05 Array Biopharma, Inc. AKT protein kinase inhibitors
CN1882347A (zh) 2003-11-21 2006-12-20 阿雷生物药品公司 Akt蛋白激酶抑制剂
GB0401269D0 (en) * 2004-01-21 2004-02-25 Astrazeneca Ab Compounds
US7288563B2 (en) 2004-02-19 2007-10-30 Bristol-Myers Squibb Company Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity
US7479496B2 (en) 2004-02-19 2009-01-20 Bristol-Myers Squibb Company Substituted spiro azabicyclics as modulators of chemokine receptor activity
US7381738B2 (en) 2004-02-19 2008-06-03 Bristol-Myers Squibb Company Substituted bicycloalkylamine derivatives as modulators of chemokine receptor activity
US7230022B2 (en) 2004-02-19 2007-06-12 Bristol-Myers Squibb Company Substituted fused bicyclic amines as modulators of chemokine receptor activity
US7435831B2 (en) 2004-03-03 2008-10-14 Chemocentryx, Inc. Bicyclic and bridged nitrogen heterocycles
CA2558211C (en) 2004-03-03 2013-09-03 Chemocentryx, Inc. Bicyclic and bridged nitrogen heterocycles
RU2006140687A (ru) * 2004-06-18 2008-07-27 Ньюросерч А/С (DK) Новые алкил-замещенные производные пиперазина и их применение в качестве ингибиторов обратного захвата моноаминовых нейротрансмиттеров
PE20060484A1 (es) * 2004-07-14 2006-07-06 Ucb Farchim Sa Preparaciones farmaceuticas liquidas que comprenden un compuesto de benzhidril piperizina
KR101220615B1 (ko) 2004-07-26 2013-01-11 메르크 세로노 에스.에이. N-히드록시아미드 유도체 및 그의 용도
US20080167321A1 (en) † 2004-09-20 2008-07-10 Xenon Pharmaceuticals Inc. Pyridine Derivatives For Inhibiting Human Stearoyl-Coa-Desaturase
US7482353B2 (en) 2005-06-15 2009-01-27 Applied Biosystems Inc. Compositions and methods pertaining to PNA synthons and oligomers comprising a universal base
KR101418024B1 (ko) * 2005-06-22 2014-07-16 케모센트릭스, 인크. 아자인다졸 화합물 및 사용방법
US7777035B2 (en) 2005-06-22 2010-08-17 Chemocentryx, Inc. Azaindazole compounds and methods of use
US7790726B2 (en) * 2005-08-16 2010-09-07 Chemocentryx, Inc. Monocyclic and bicyclic compounds and methods of use
WO2007044885A2 (en) 2005-10-11 2007-04-19 Chemocentryx, Inc. Piperidine derivatives and methods of use
EP1847543A1 (de) 2006-04-19 2007-10-24 Boehringer Ingelheim Pharma GmbH & Co. KG Dihydrothienopyrimidine zur Behandlung von entzündlichen Erkrankungen
WO2007146230A2 (en) * 2006-06-14 2007-12-21 Merck & Co., Inc. Non-nucleoside reverse transcriptase inhibitors
EP2044043B2 (de) 2006-06-16 2021-03-03 H. Lundbeck A/S 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazin hydrobromid als verbindung mit kombinierter serotoninwiederaufnahme-, 5-ht3- und 5-ht1a-aktivität zur behandlung kognitiver störungen
US20090252779A1 (en) * 2006-06-22 2009-10-08 Chemocentryx, Inc. Azaindazole compounds and methods of use
EA015529B1 (ru) 2007-05-22 2011-08-30 Кемосентрикс, Инк. 3-(имидазолил)пиразоло[3,4-b]пиридины
WO2009015166A1 (en) 2007-07-24 2009-01-29 Bristol-Myers Squibb Company Piperidine derivatives as modulators of chemokine receptor activity
EP2285783B1 (de) 2008-04-29 2014-05-21 Boehringer Ingelheim International GmbH Indazolverbindungen als ccr1-rezeptorantagonisten
BRPI0910837B1 (pt) * 2008-04-30 2017-03-07 Bayer Cropscience Ag ésteres e tioésteres tiazol-4-carboxílicos, seus usos, e método e composição para controlar fungos fitopatogênicos prejudiciais
EP2297112B1 (de) * 2008-05-06 2013-04-03 Boehringer Ingelheim International GmbH Pyrazolverbindungen als ccr1-antagonisten
TWI433838B (zh) 2008-06-25 2014-04-11 必治妥美雅史谷比公司 作為趨化因子受體活性調節劑之六氫吡啶衍生物
US8343975B2 (en) 2008-09-11 2013-01-01 Penglie Zhang 4-amino-3-(imidazolyl)-pyrazolo[3,4-D]pyrimidines
CA2737472A1 (en) * 2008-09-26 2010-04-01 Boehringer Ingelheim International Gmbh Azaindazole compounds as ccr1 receptor antagonists
EP2352501B1 (de) * 2008-11-03 2014-01-01 ChemoCentryx, Inc. Verbindung zur verwendung in der behandlung von osteoporose
US8362249B2 (en) * 2009-04-27 2013-01-29 Boehringer Ingelheim International Gmbh CXCR3 receptor antagonists
EP2424840B1 (de) * 2009-04-27 2014-08-06 Boehringer Ingelheim International GmbH Cxcr3-rezeptor antagonisten
WO2011049917A1 (en) 2009-10-21 2011-04-28 Boehringer Ingelheim International Gmbh Indazole and pyrazolopyridine compounds as ccr1 receptor antagonists
WO2011056440A1 (en) 2009-10-27 2011-05-12 Boehringer Ingelheim International Gmbh Heterocyclic compounds as ccr1 receptor antagonists
JP2013517281A (ja) * 2010-01-13 2013-05-16 テンペロ、ファーマシューティカルズ、インコーポレイテッド 化合物及び方法
JP5793182B2 (ja) 2010-04-30 2015-10-14 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃｃｒ１受容体アンタゴニストとしてのアザインダゾールアミド化合物
EP2655371B1 (de) 2010-12-23 2015-02-25 Boehringer Ingelheim International GmbH Pyrazolopiperidinverbindungen als ccr1-rezeptorantagonisten
CA2852160A1 (en) 2011-10-28 2013-05-02 Galderma Research & Development New leukocyte infiltrate markers for rosacea and uses thereof
US8822464B2 (en) * 2011-11-28 2014-09-02 Boehringer Ingelheim International Gmbh N-aryl-piperazine derivatives and their use as positive allosteric modulators of mGluR5 receptors
US8741892B2 (en) 2011-12-05 2014-06-03 Boehringer Ingelheim International Gmbh Compounds
US8642774B2 (en) 2011-12-08 2014-02-04 Boehringer Ingelheim International Gmbh Compounds
US8796467B2 (en) 2011-12-13 2014-08-05 Boehringer Ingelheim International Gmbh Compounds
US8846948B2 (en) 2011-12-13 2014-09-30 Boehringer Ingelheim International Gmbh Compounds
US8937176B2 (en) 2011-12-14 2015-01-20 Boehringer Ingelheim International Gmbh Compounds
US8716277B2 (en) 2011-12-14 2014-05-06 Boehringer Ingelheim International Gmbh Substituted imidazole compounds useful as positive allosteric modulators of mGlu5 receptor activity
US8883789B2 (en) 2011-12-14 2014-11-11 Boehringer Ingelheim International Gmbh Piperazine derivatives and their use as positive allosteric modulators of mGluR5 receptors
US8889677B2 (en) 2012-01-17 2014-11-18 Boehringer Ingellheim International GmbH Substituted triazoles useful as mGlu5 receptor modulators
ES2671323T3 (es) 2013-07-22 2018-06-06 Idorsia Pharmaceuticals Ltd Derivados 1¿(piperazin¿1¿il)¿2¿([1,2,4]triazol¿1¿il)¿etanona
AR099789A1 (es) 2014-03-24 2016-08-17 Actelion Pharmaceuticals Ltd Derivados de 8-(piperazin-1-il)-1,2,3,4-tetrahidro-isoquinolina
PL3245203T3 (pl) 2015-01-15 2019-05-31 Idorsia Pharmaceuticals Ltd Pochodne hydroksyalkilopiperazyny jako modulatory receptora cxcr3
AR103399A1 (es) 2015-01-15 2017-05-10 Actelion Pharmaceuticals Ltd Derivados de (r)-2-metil-piperazina como moduladores del receptor cxcr3
EP3474667A4 (de) * 2016-06-23 2019-11-27 St. Jude Children's Research Hospital, Inc. Kleinmolekülige modulatoren von pantothenatkinasen
BR112020012875A2 (pt) 2017-12-27 2021-01-05 St. Jude Children¿S Research Hospital, Inc. Moduladores de pequenas moléculas das pantotenato quinases
WO2019133632A1 (en) 2017-12-27 2019-07-04 St. Jude Children's Research Hospital Methods of treating disorders associated with castor
US11872217B2 (en) 2019-07-10 2024-01-16 Chemocentryx, Inc. Indanes as PD-L1 inhibitors
WO2021039961A1 (ja) * 2019-08-30 2021-03-04 大日本住友製薬株式会社 縮環ピラゾール誘導体

Family Cites Families (91)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE663344A (de) * 1964-05-04
US3362956A (en) * 1965-08-19 1968-01-09 Sterling Drug Inc 1-[(heterocyclyl)-lower-alkyl]-4-substituted-piperazines
US3491098A (en) * 1967-05-29 1970-01-20 Sterling Drug Inc 1-((imidazolyl)-lower-alkyl)-4-substituted-piperazines
US3778433A (en) * 1969-04-18 1973-12-11 Sumitomo Chemical Co Process for producing benzodiazepine derivatives
DE2247187A1 (de) * 1972-09-26 1974-03-28 Bayer Ag Imidazolylessigsaeureamide, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel
JPS5944313B2 (ja) * 1974-11-26 1984-10-29 中外製薬株式会社 インダゾ−ル誘導体の製法
US3994890A (en) * 1974-01-31 1976-11-30 Chugai Seiyaku Kabushiki Kaisha 1-Aminoalkyl, 3-phenyl indazoles
US4174393A (en) * 1975-07-09 1979-11-13 Duphar International Research B.V. 1,3,4-Substituted pyrazoline derivatives
US4166452A (en) * 1976-05-03 1979-09-04 Generales Constantine D J Jr Apparatus for testing human responses to stimuli
US4256108A (en) * 1977-04-07 1981-03-17 Alza Corporation Microporous-semipermeable laminated osmotic system
US4243619A (en) * 1978-03-31 1981-01-06 Union Carbide Corporation Process for making film from low density ethylene hydrocarbon copolymer
US4310429A (en) * 1978-06-19 1982-01-12 The B. F. Goodrich Company Stabilized polymers, novel stabilizers, and synthesis thereof
DE2842539A1 (de) * 1978-09-29 1980-04-10 Bayer Ag 1-isocyanato-anthrachinone
US4265874A (en) 1980-04-25 1981-05-05 Alza Corporation Method of delivering drug with aid of effervescent activity generated in environment of use
DE3132915A1 (de) * 1981-08-20 1983-03-03 Kali-Chemie Pharma Gmbh, 3000 Hannover 1,5-diphenylpyrazolin-3-on-verbindungen sowie verfahren und zwischenprodukte zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
JPS5852256A (ja) * 1981-09-24 1983-03-28 Nippon Nohyaku Co Ltd 置換又は非置換脂肪酸アミド誘導体及びその塩類
DE3306771A1 (de) * 1983-02-25 1984-08-30 Bayer Ag, 5090 Leverkusen Chinoloncarbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel
US4547505A (en) 1983-03-25 1985-10-15 Degussa Aktiengesellschaft N-Phenyl-N-'-cycloalkylalkanoylpiperazine useful as analgetics and process for its production
US4562189A (en) * 1984-10-09 1985-12-31 American Cyanamid Company Pyrazolylpiperazines
DE3442860A1 (de) * 1984-11-24 1986-05-28 Kali-Chemie Pharma Gmbh, 3000 Hannover 5-alkyl-1-phenyl-2-piperazinoalkylpyrazolin-3- on-verbindungen sowie verfahren und zwischenprodukte zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
ZA871335B (en) * 1986-02-27 1987-09-30 Duphar Int Res New aryl-substituted(n-piperidinyl)methyl-and(n-piperazinyl)-methylazoles having antipsychotic properties
IL85700A0 (en) * 1987-03-24 1988-08-31 Takeda Chemical Industries Ltd 1,4-disubstituted piperazine compounds,their production and use
US4997836A (en) * 1988-11-11 1991-03-05 Takeda Chemical Industries, Ltd. Trisubstituted piperazine compounds, their production and use
EP0385043A1 (de) * 1989-02-28 1990-09-05 Fabrica Espanola De Productos Quimicos Y Farmaceuticos, S.A. (Faes) 4-Substituierte Piperazinderivate
US5215989A (en) * 1989-12-08 1993-06-01 Merck & Co., Inc. Nitrogen-containing heterocyclic compounds as class III antiarrhythmic agents
FR2672052B1 (fr) * 1991-01-28 1995-05-24 Esteve Labor Dr Derives d'aryl (ou heteroaryl)-piperazinyl-alkyl-azoles, leur preparation et leur application en tant que medicaments.
GB9021535D0 (en) * 1990-10-03 1990-11-14 Wyeth John & Brother Ltd Piperazine derivatives
GB9021453D0 (en) * 1990-10-03 1990-11-14 Wyeth John & Brother Ltd Piperazine derivatives
FR2673628B1 (fr) * 1991-03-07 1993-07-09 Esteve Labor Dr Procede de preparation de derives d'aryl (ou heteroaryl)-piperazinyl-butyl-azoles.
GB9305623D0 (en) * 1993-03-18 1993-05-05 Merck Sharp & Dohme Therapeutic agents
US5681954A (en) * 1993-05-14 1997-10-28 Daiichi Pharmaceutical Co., Ltd. Piperazine derivatives
US5464788A (en) * 1994-03-24 1995-11-07 Merck & Co., Inc. Tocolytic oxytocin receptor antagonists
US5486534A (en) * 1994-07-21 1996-01-23 G. D. Searle & Co. 3,4-substituted pyrazoles for the treatment of inflammation
US5607936A (en) * 1994-09-30 1997-03-04 Merck & Co., Inc. Substituted aryl piperazines as neurokinin antagonists
US5719156A (en) * 1995-05-02 1998-02-17 Schering Corporation Piperazino derivatives as neurokinin antagonists
JP4108747B2 (ja) * 1995-07-13 2008-06-25 アボット ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト 治療薬としてのピペラジン誘導体
GB9518552D0 (en) 1995-09-11 1995-11-08 Fujisawa Pharmaceutical Co New heterocyclic compounds
US5760028A (en) * 1995-12-22 1998-06-02 The Dupont Merck Pharmaceutical Company Integrin receptor antagonists
US5646151A (en) * 1996-03-08 1997-07-08 Adolor Corporation Kappa agonist compounds and pharmaceutical formulations thereof
WO1997044329A1 (en) 1996-05-20 1997-11-27 Teijin Limited Diarylalkyl cyclic diamine derivatives as chemokine receptor antagonists
US5760225A (en) * 1996-11-15 1998-06-02 Neurogen Corporation Certain pyrazole derivatives as corticotropin-releasing factor receptor CRF1 specific ligands
DE69720051T2 (de) * 1996-12-03 2003-09-04 Banyu Pharmaceutical Co., Ltd. Harnstoffderivate
WO1998025617A1 (en) 1996-12-13 1998-06-18 Merck & Co., Inc. Substituted aryl piperazines as modulators of chemokine receptor activity
JP4095676B2 (ja) 1997-03-03 2008-06-04 エーザイ株式会社 注意障害を治療するためのコリンエステラーゼ阻害剤の使用
US6979686B1 (en) 2001-12-07 2005-12-27 Pharmacia Corporation Substituted pyrazoles as p38 kinase inhibitors
US6207665B1 (en) * 1997-06-12 2001-03-27 Schering Aktiengesellschaft Piperazine derivatives and their use as anti-inflammatory agents
US5968938A (en) * 1997-06-18 1999-10-19 Merck & Co., Inc. Piperazine oxytocin receptor antagonists
ES2125206B1 (es) * 1997-07-21 1999-11-16 Esteve Labor Dr Derivados de acil-piperazinil-pirimidinas, su preparacion y su aplicacion como medicamentos.
GB9716657D0 (en) 1997-08-07 1997-10-15 Zeneca Ltd Chemical compounds
CA2298813A1 (en) 1997-08-28 1999-03-04 Merck & Co., Inc. Pyrrolidine and piperidine modulators of chemokine receptor activity
US6384035B1 (en) * 1997-10-09 2002-05-07 Ortho-Mcneil Pharmaceutical, Inc. Heterocycles useful in the treatment of benign prostatic hyperplasia
PL192083B1 (pl) 1997-11-18 2006-08-31 Dupont Pharmaceuticals Res Lab Pochodne amin cyklicznych i ich zastosowanie
ZA9811576B (en) 1997-12-19 2000-06-19 Takeda Chemical Industries Ltd Anilide derivative, production and use thereof.
CA2319077A1 (en) 1998-01-21 1999-07-29 Yoshisuke Nakasato Chemokine receptor antagonists and methods of use therefor
EP1047675A1 (de) 1998-01-21 2000-11-02 Millennium Pharmaceuticals, Inc. Chemokinrezeptor-antagonisten und verfahren zur verwendund
DE69920888T2 (de) * 1998-03-27 2006-02-02 Bristol-Myers Squibb Pharma Co. Disubstituierte pyrazoline und triazoline als faktor xa inhibitoren
US6492375B2 (en) * 1998-06-30 2002-12-10 Neuromed Technologies, Inc. Partially saturated calcium channel blockers
US6288083B1 (en) * 1998-09-04 2001-09-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
CA2350903A1 (en) 1998-11-20 2000-06-02 F. Hoffmann-La Roche Ag Pyrrolidine derivatives-ccr-3 receptor antagonists
GB9902459D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902461D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902452D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
GB9902453D0 (en) 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds
JP3533134B2 (ja) 1999-02-15 2004-05-31 三井化学株式会社 フッ素化剤及びその製法と使用
GB9905010D0 (en) * 1999-03-04 1999-04-28 Merck Sharp & Dohme Therapeutic agents
WO2000053600A1 (fr) 1999-03-11 2000-09-14 Banyu Pharmaceutical Co., Ltd. Derives piperidiniques
AU4796700A (en) 1999-05-13 2000-12-05 Dupont Pharmaceuticals Research Laboratories, Inc. Ureido-substituted cyclic amine derivatives and their use as drug
US6492516B1 (en) 1999-05-14 2002-12-10 Merck & Co., Inc. Compounds having cytokine inhibitory activity
ATE277903T1 (de) 1999-05-14 2004-10-15 Bristol Myers Squibb Pharma Re Zyklische aminderivate und ihre verwendung
ES2293980T3 (es) * 2000-01-13 2008-04-01 Amgen Inc. Agentes antibacterianos.
AU2001250404A1 (en) * 2000-03-27 2001-10-08 Basf Aktiengesellschaft Use of dopamine-d3 receptor ligands for the treatment of diseases of the central nervous system
KR20020084273A (ko) * 2000-03-31 2002-11-04 화이자 프로덕츠 인코포레이티드 신규한 피페라진 유도체
US20020045613A1 (en) * 2000-04-27 2002-04-18 Heinz Pauls 1-aroyl-piperidinyl benzamidines
US6673923B2 (en) * 2000-05-03 2004-01-06 Tularik Inc. Pyrazole antimicrobial agents
AU2001269821A1 (en) * 2000-06-15 2001-12-24 Barbara Chen Cycloalkyl alkanoic acids as integrin receptor antagonists
GB0017256D0 (en) * 2000-07-13 2000-08-30 Merck Sharp & Dohme Therapeutic agents
KR20030024799A (ko) 2000-07-20 2003-03-26 뉴로젠 코포레이션 캡사이신 수용체 리간드
EP1309591B1 (de) * 2000-08-14 2007-01-24 Ortho-McNeil Pharmaceutical, Inc. Substituierte pyrazole
EA200300392A1 (ru) * 2000-10-19 2003-10-30 Пфайзер Продактс Инк. Производные пиперазина с мостиковой связью
US6451399B1 (en) 2001-02-05 2002-09-17 Daniel G. Boyce Display mat
CA2440803A1 (en) 2001-03-07 2002-09-12 Pfizer Products Inc. Modulators of chemokine receptor activity
CN1157388C (zh) * 2001-05-29 2004-07-14 北京大学 哌嗪基二硫代甲酸酯类化合物,它们的制备方法和在抗肿瘤药物中的应用
ES2180456B1 (es) * 2001-07-20 2004-05-01 Laboratorios S.A.L.V.A.T., S.A. Isoxazoles sustituidos y su utilizacion como antibioticos.
WO2003024450A1 (en) 2001-09-20 2003-03-27 Eisai Co., Ltd. Methods for treating prion diseases
US7067517B2 (en) 2001-12-14 2006-06-27 Nero Nordisk A/S Use of compounds for decreasing activity of hormone-sensitive lipase
NO315724B1 (no) * 2001-12-20 2003-10-13 Sten Hellvik Datainnsamlingssystem for et fartöy
JP4723242B2 (ja) 2002-06-12 2011-07-13 ケモセントリックス インコーポレーティッド 炎症および免疫障害治療用ｃｃｒ１アンタゴニストとして使用するための１−アリール−４−置換ピペラジン誘導体
US20050256130A1 (en) 2002-06-12 2005-11-17 Chemocentryx, Inc. Substituted piperazines
US7842693B2 (en) * 2002-06-12 2010-11-30 Chemocentryx, Inc. Substituted piperazines
PA8575901A1 (es) 2002-07-18 2004-07-20 Pfizer Prod Inc Derivados de piperidina novedosos
MXPA05001334A (es) * 2002-08-02 2005-09-08 Argenta Discovery Ltd Acidos tienil-hidroxamicos sustituidos como inhibidores de la desacetilasa de histona.

Also Published As

Publication number Publication date
US20040082571A1 (en) 2004-04-29
CA2488202A1 (en) 2003-12-24
CN1867336A (zh) 2006-11-22
MXPA04012393A (es) 2005-06-17
WO2003105853A1 (en) 2003-12-24
DK1531822T3 (da) 2009-12-07
EP1531822A1 (de) 2005-05-25
AU2003236500A1 (en) 2003-12-31
KR101255356B1 (ko) 2013-04-17
ATE438401T1 (de) 2009-08-15
AU2003236500B9 (en) 2009-07-02
CN1867336B (zh) 2010-05-12
JP2006508036A (ja) 2006-03-09
DE60328690D1 (de) 2009-09-17
ES2329356T3 (es) 2009-11-25
CA2488202C (en) 2011-03-08
HK1099206A1 (en) 2007-08-10
US7157464B2 (en) 2007-01-02
US7449576B1 (en) 2008-11-11
AU2003236500B2 (en) 2009-01-08
KR20050042754A (ko) 2005-05-10
JP4723242B2 (ja) 2011-07-13
US20080261987A1 (en) 2008-10-23

Similar Documents

Publication Publication Date Title
EP1531822B1 (de) 1-aryl-4-substituierte piperazin-derivate zur verwendung als ccr1-antagonisten zur behandlung von entzündungen und immunerkrankungen
US7842693B2 (en) Substituted piperazines
AU2004296879B2 (en) Substituted piperazines
US8324216B2 (en) Substituted piperazines
EP1720545B1 (de) Bizyklische und überbrückte stickstoff-heterozyklen
EP1906965B1 (de) Azaindazol-verbindungen und anwendungsverfahren
AU621461B2 (en) 4,5,6-Substituted-N-(substituted-phenyl)-2-pyrimidinamines
EP2323663B1 (de) 4-amino-3-(imidazolyl)-pyrazolo-[3,4-d]-pyrimidine
DK2935227T3 (en) DIAZOLAMIDES AS CCR1 RECEPTOR ANTAGONISTS
CN100542534C (zh) 取代的哌嗪
MXPA06006518A (es) Piperazinas sustituidas.
CN116396278A (zh) 作为多巴胺d3受体选择性调节剂的咔唑类衍生物

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20041222

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: CHEMOCENTRYX, INC.

17Q First examination report despatched

Effective date: 20060426

RIN1 Information on inventor provided before grant (corrected)

Inventor name: PENNELL, ANDREW, M., K.

Inventor name: MCMASTER, BRIAN, E.

Inventor name: SEN, SUBRABRATA

Inventor name: AGGEN, JAMES, B.

Inventor name: DAIRAGHI, DANIEL, JOSEPH

Inventor name: WRIGHT, J., J., KIM

RIN1 Information on inventor provided before grant (corrected)

Inventor name: SEN, SUBRABRATA

Inventor name: MCMASTER, BRIAN, E.

Inventor name: DAIRAGHI, DANIEL, JOSEPH

Inventor name: WRIGHT, J., J., KIM

Inventor name: MARTICHONOK, VALERI V.

Inventor name: PENNELL, ANDREW, M., K.

Inventor name: AGGEN, JAMES, B.

RIN1 Information on inventor provided before grant (corrected)

Inventor name: MARTICHONOK, VALERI V.

Inventor name: MCMASTER, BRIAN, E.

Inventor name: SEN, SUBHABRATA

Inventor name: WRIGHT, J., J., KIM

Inventor name: DAIRAGHI, DANIEL, JOSEPH

Inventor name: AGGEN, JAMES, B.

Inventor name: PENNELL, ANDREW, M., K.

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL LT LV MK

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: KIRKER & CIE S.A.

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 60328690

Country of ref document: DE

Date of ref document: 20090917

Kind code of ref document: P

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2329356

Country of ref document: ES

Kind code of ref document: T3

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

LTIE Lt: invalidation of european patent or patent extension

Effective date: 20090805

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090805

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090805

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20091105

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20091205

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090805

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090805

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090805

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090805

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20100507

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20091106

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090805

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100611

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20100206

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20090805

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 14

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 15

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DK

Payment date: 20180612

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20180417

Year of fee payment: 16

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IE

Payment date: 20190610

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 20190611

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20190614

Year of fee payment: 17

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

Effective date: 20190630

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 438401

Country of ref document: AT

Kind code of ref document: T

Effective date: 20190611

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20190630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190611

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190630

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: NL

Ref legal event code: MM

Effective date: 20200701

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200701

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200630

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200630

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200611

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200612

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20220510

Year of fee payment: 20

Ref country code: GB

Payment date: 20220425

Year of fee payment: 20

Ref country code: FR

Payment date: 20220408

Year of fee payment: 20

Ref country code: DE

Payment date: 20220420

Year of fee payment: 20

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20220706

Year of fee payment: 20

REG Reference to a national code

Ref country code: DE

Ref legal event code: R071

Ref document number: 60328690

Country of ref document: DE

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20230626

REG Reference to a national code

Ref country code: GB

Ref legal event code: PE20

Expiry date: 20230610

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20230612

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION

Effective date: 20230610